Bio

Academic Appointments


Community and International Work


  • collaboration with Italian geneticists, Italy

    Topic

    Study of Italian surnames, others.

    Partnering Organization(s)

    Institute of Molecular Genetics, CNR, Pavia

    Populations Served

    Italian

    Location

    International

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    Yes

Research & Scholarship

Current Research and Scholarly Interests


My research is dedicated to the study of the origin of modern humans and their evolutionary history by using genetic markers. Presently, the laboratory is concentrating on the study of Y chromosomes. My personal interest has also been dedicated for a long time to a multidisciplinary approach to human evolution, including demography, archeology, linguistics, anthropology, surnames, and to the interactions of genetic and cultural evolution.

Publications

All Publications


  • Polarity and temporality of high-resolution Y-chromosome distributions in India identify both indigenous and exogenous expansions and reveal minor genetic influence of central Asian pastoralists AMERICAN JOURNAL OF HUMAN GENETICS Sengupta, S., Zhivotovsky, L. A., King, R., Mehdi, S. Q., Edmonds, C. A., Chow, C. E., Lin, A. A., Mitra, M., Sil, S. K., Ramesh, A., Rani, M. V., Thakur, C. M., Cavalli-Sforza, L. L., Majumder, P. P., Underhill, P. A. 2006; 78 (2): 202-221

    Abstract

    Although considerable cultural impact on social hierarchy and language in South Asia is attributable to the arrival of nomadic Central Asian pastoralists, genetic data (mitochondrial and Y chromosomal) have yielded dramatically conflicting inferences on the genetic origins of tribes and castes of South Asia. We sought to resolve this conflict, using high-resolution data on 69 informative Y-chromosome binary markers and 10 microsatellite markers from a large set of geographically, socially, and linguistically representative ethnic groups of South Asia. We found that the influence of Central Asia on the pre-existing gene pool was minor. The ages of accumulated microsatellite variation in the majority of Indian haplogroups exceed 10,000-15,000 years, which attests to the antiquity of regional differentiation. Therefore, our data do not support models that invoke a pronounced recent genetic input from Central Asia to explain the observed genetic variation in South Asia. R1a1 and R2 haplogroups indicate demographic complexity that is inconsistent with a recent single history. Associated microsatellite analyses of the high-frequency R1a1 haplogroup chromosomes indicate independent recent histories of the Indus Valley and the peninsular Indian region. Our data are also more consistent with a peninsular origin of Dravidian speakers than a source with proximity to the Indus and with significant genetic input resulting from demic diffusion associated with agriculture. Our results underscore the importance of marker ascertainment for distinguishing phylogenetic terminal branches from basal nodes when attributing ancestral composition and temporality to either indigenous or exogenous sources. Our reappraisal indicates that pre-Holocene and Holocene-era--not Indo-European--expansions have shaped the distinctive South Asian Y-chromosome landscape.

    View details for Web of Science ID 000236744900003

    View details for PubMedID 16400607

  • The role of selection in the evolution of human mitochondrial genomes GENETICS Kivisild, T., Shen, P. D., Wall, D. P., Do, B., Sung, R., Davis, K., Passarino, G., Underhill, P. A., Scharfe, C., Torroni, A., Scozzari, R., Modiano, D., Coppa, A., de Knijff, P., Feldman, M., Cavalli-Sforza, L. L., Oefner, P. J. 2006; 172 (1): 373-387

    Abstract

    High mutation rate in mammalian mitochondrial DNA generates a highly divergent pool of alleles even within species that have dispersed and expanded in size recently. Phylogenetic analysis of 277 human mitochondrial genomes revealed a significant (P < 0.01) excess of rRNA and nonsynonymous base substitutions among hotspots of recurrent mutation. Most hotspots involved transitions from guanine to adenine that, with thymine-to-cytosine transitions, illustrate the asymmetric bias in codon usage at synonymous sites on the heavy-strand DNA. The mitochondrion-encoded tRNAThr varied significantly more than any other tRNA gene. Threonine and valine codons were involved in 259 of the 414 amino acid replacements observed. The ratio of nonsynonymous changes from and to threonine and valine differed significantly (P = 0.003) between populations with neutral (22/58) and populations with significantly negative Tajima's D values (70/76), independent of their geographic location. In contrast to a recent suggestion that the excess of nonsilent mutations is characteristic of Arctic populations, implying their role in cold adaptation, we demonstrate that the surplus of nonsynonymous mutations is a general feature of the young branches of the phylogenetic tree, affecting also those that are found only in Africa. We introduce a new calibration method of the mutation rate of synonymous transitions to estimate the coalescent times of mtDNA haplogroups.

    View details for DOI 10.1534/genetics.105.043901

    View details for Web of Science ID 000235197700033

    View details for PubMedID 16172508

  • Support from the relationship of genetic and geographic distance in human populations for a serial founder effect originating in Africa PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Ramachandran, S., Deshpande, O., Roseman, C. C., Rosenberg, N. A., Feldman, M. W., Cavalli-Sforza, L. L. 2005; 102 (44): 15942-15947

    Abstract

    Equilibrium models of isolation by distance predict an increase in genetic differentiation with geographic distance. Here we find a linear relationship between genetic and geographic distance in a worldwide sample of human populations, with major deviations from the fitted line explicable by admixture or extreme isolation. A close relationship is shown to exist between the correlation of geographic distance and genetic differentiation (as measured by F(ST)) and the geographic pattern of heterozygosity across populations. Considering a worldwide set of geographic locations as possible sources of the human expansion, we find that heterozygosities in the globally distributed populations of the data set are best explained by an expansion originating in Africa and that no geographic origin outside of Africa accounts as well for the observed patterns of genetic diversity. Although the relationship between F(ST) and geographic distance has been interpreted in the past as the result of an equilibrium model of drift and dispersal, simulation shows that the geographic pattern of heterozygosities in this data set is consistent with a model of a serial founder effect starting at a single origin. Given this serial-founder scenario, the relationship between genetic and geographic distance allows us to derive bounds for the effects of drift and natural selection on human genetic variation.

    View details for Web of Science ID 000233090900042

    View details for PubMedID 16243969

  • Fisher's theorems for multivariable, time- and space-dependent systems, with applications in population genetics and chemical kinetics PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Vlad, M. O., Szedlacsek, S. E., Pourmand, N., Cavalli-Sforza, L. L., Oefner, P., Ross, J. 2005; 102 (28): 9848-9853

    Abstract

    We study different physical, chemical, or biological processes involving replication, transformation, and disappearance processes, as well as transport processes, and assume that the time and space dependence of the species densities are known. We derive two types of Fisher equations. The first type relates the average value of the time derivative of the relative time-specific rates of growth of the different species to the variance of the relative, time-specific rates of growth. A second type relates the average value of the gradient or the divergence of the relative, space-specific rates of growth to the space correlation matrix of the relative, space-specific rates of growth. These Fisher equations are exact results, which are independent of the detailed kinetics of the process: they are valid whether the evolution equations are linear or nonlinear, local or nonlocal in space and/or time and can be applied for the study of a large class of physical, chemical, and biological systems described in terms of time- and/or space-dependent density fields. We examine the implications of our generalized Fisher relations in population genetics, biochemistry, and chemical kinetics (reaction-diffusion systems). We show that there is a connection between the enhanced (hydrodynamic) transport of mutations induced by population growth and space-specific rate vectors: the velocity of enhanced transport is proportional to the product of the diffusion coefficient of the species and the space rate vector; this relation is similar to a fluctuation-dissipation relation in statistical mechanics.

    View details for DOI 10.1073/pnas.0504073102

    View details for Web of Science ID 000230545100022

    View details for PubMedID 15994224

  • Opinion - The Human Genome Diversity Project: past, present and future NATURE REVIEWS GENETICS Cavalli-Sforza, L. L. 2005; 6 (4): 333-340

    Abstract

    The Human Genome Project, in accomplishing its goal of sequencing one human genome, heralded a new era of research, a component of which is the systematic study of human genetic variation. Despite delays, the Human Genome Diversity Project has started to make progress in understanding the patterns of this variation and its causes, and also promises to provide important information for biomedical studies.

    View details for DOI 10.1038/nrg1579

    View details for Web of Science ID 000228093000018

    View details for PubMedID 15803201

  • Enhanced (hydrodynamic) transport induced by population growth in reaction-diffusion systems with application to population genetics PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Vlad, M. O., Cavalli-Sforza, L. L., Ross, J. 2004; 101 (28): 10249-10253

    Abstract

    We consider a system made up of different physical, chemical, or biological species undergoing replication, transformation, and disappearance processes, as well as slow diffusive motion. We show that for systems with net growth the balance between kinetics and the diffusion process may lead to fast, enhanced hydrodynamic transport. Solitary waves in the system, if they exist, stabilize the enhanced transport, leading to constant transport speeds. We apply our theory to the problem of determining the original mutation position from the current geographic distribution of a given mutation. We show that our theory is in good agreement with a simulation study of the mutation problem presented in the literature. It is possible to evaluate migratory trajectories from measured data related to the current distribution of mutations in human populations.

    View details for DOI 10.1073/pnas.0403419101

    View details for Web of Science ID 000222664200003

    View details for PubMedID 15231998

  • Mutations arising in the wave front of an expanding population PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Edmonds, C. A., Lillie, A. S., Cavalli-Sforza, L. L. 2004; 101 (4): 975-979

    Abstract

    The ability to infer the time and place of origin of a mutation can be very useful when reconstructing the evolutionary histories of populations and species. We use forward computer simulations of population growth, migration, and mutation in an analysis of an expanding population with a wave front that advances at a constant slow rate. A pronounced founder effect can be observed among mutations arising in this wave front where extreme population bottlenecks arise and are followed by major population growth. A fraction of mutations travel with the wave front and generate mutant populations that are on average much larger than those that remain stationary. Analysis of the diffusion of these mutants makes it possible to reconstruct migratory trajectories during population expansions, thus helping us better understand observed patterns in the evolution of species such as modern humans. Examination of some historical data supports our model.

    View details for DOI 10.1073/pnas.0308064100

    View details for Web of Science ID 000188533600015

    View details for PubMedID 14732681

  • Excavating Y-chromosome haplotype strata in Anatolia HUMAN GENETICS Cinnioglu, C., King, R., Kivisild, T., Kalfoglu, E., Atasoy, S., Cavalleri, G. L., Lillie, A. S., Roseman, C. C., Lin, A. A., Prince, K., Oefner, P. J., Shen, P. D., Semino, O., Cavalli-Sforza, L. L., Underhill, P. A. 2004; 114 (2): 127-148

    Abstract

    Analysis of 89 biallelic polymorphisms in 523 Turkish Y chromosomes revealed 52 distinct haplotypes with considerable haplogroup substructure, as exemplified by their respective levels of accumulated diversity at ten short tandem repeat (STR) loci. The major components (haplogroups E3b, G, J, I, L, N, K2, and R1; 94.1%) are shared with European and neighboring Near Eastern populations and contrast with only a minor share of haplogroups related to Central Asian (C, Q and O; 3.4%), Indian (H, R2; 1.5%) and African (A, E3*, E3a; 1%) affinity. The expansion times for 20 haplogroup assemblages was estimated from associated STR diversity. This comprehensive characterization of Y-chromosome heritage addresses many multifaceted aspects of Anatolian prehistory, including: (1) the most frequent haplogroup, J, splits into two sub-clades, one of which (J2) shows decreasing variances with increasing latitude, compatible with a northward expansion; (2) haplogroups G1 and L show affinities with south Caucasus populations in their geographic distribution as well as STR motifs; (3) frequency of haplogroup I, which originated in Europe, declines with increasing longitude, indicating gene flow arriving from Europe; (4) conversely, haplogroup G2 radiates towards Europe; (5) haplogroup E3b3 displays a latitudinal correlation with decreasing frequency northward; (6) haplogroup R1b3 emanates from Turkey towards Southeast Europe and Caucasia and; (7) high resolution SNP analysis provides evidence of a detectable yet weak signal (<9%) of recent paternal gene flow from Central Asia. The variety of Turkish haplotypes is witness to Turkey being both an important source and recipient of gene flow.

    View details for DOI 10.1007/s00439-003-1031-4

    View details for Web of Science ID 000186954300001

    View details for PubMedID 14586639

  • Immunology: hepatitis A virus link to atopic disease. Nature McIntire, J. J., Umetsu, S. E., Macaubas, C., Hoyte, E. G., Cinnioglu, C., Cavalli-Sforza, L. L., Barsh, G. S., Hallmayer, J. F., Underhill, P. A., Risch, N. J., Freeman, G. J., DeKruyff, R. H., Umetsu, D. T. 2003; 425 (6958): 576-?

    View details for PubMedID 14534576

  • The application of molecular genetic approaches to the study of human evolution NATURE GENETICS Cavalli-Sforza, L. L., Feldman, M. W. 2003; 33: 266-275

    Abstract

    The past decade of advances in molecular genetic technology has heralded a new era for all evolutionary studies, but especially the science of human evolution. Data on various kinds of DNA variation in human populations have rapidly accumulated. There is increasing recognition of the importance of this variation for medicine and developmental biology and for understanding the history of our species. Haploid markers from mitochondrial DNA and the Y chromosome have proven invaluable for generating a standard model for evolution of modern humans. Conclusions from earlier research on protein polymorphisms have been generally supported by more sophisticated DNA analysis. Co-evolution of genes with language and some slowly evolving cultural traits, together with the genetic evolution of commensals and parasites that have accompanied modern humans in their expansion from Africa to the other continents, supports and supplements the standard model of genetic evolution. The advances in our understanding of the evolutionary history of humans attests to the advantages of multidisciplinary research.

    View details for DOI 10.1038/ng1113

    View details for Web of Science ID 000181390900007

    View details for PubMedID 12610536

  • Neutrality condition and response law for nonlinear reaction-diffusion equations, with application to population genetics PHYSICAL REVIEW E Vlad, M. O., Moran, F., Tsuchiya, M., Cavalli-Sforza, L. L., Oefner, P. J., Ross, J. 2002; 65 (6)

    Abstract

    We study a general class of nonlinear macroscopic evolution equations with "transport" and "reaction" terms which describe the dynamics of a species of moving individuals (atoms, molecules, quasiparticles, organisms, etc.). We consider that two types of individuals exist, "not marked" and "marked," respectively. We assume that the concentrations of both types of individuals are measurable and that they obey a neutrality condition, that is, the kinetic and transport properties of the "not marked" and "marked" individuals are identical. We suggest a response experiment, which consists in varying the fraction of "marked" individuals with the preservation of total fluxes, and show that the response of the system can be represented by a linear superposition law even though the underlying dynamics of the system is in general highly nonlinear. The linear response law is valid even for large perturbations and is not the result of a linearization procedure but rather a necessary consequence of the neutrality condition. First, we apply the response theorem to chemical kinetics, where the "marked species" is a molecule labeled with a radioactive isotope and there is no kinetic isotope effect. The susceptibility function of the response law can be related to the reaction mechanism of the process. Secondly we study the geographical distribution of the nonrecurrent, nonreversible neutral mutations of the nonrecombining portion of the Y chromosome from human populations and show that the fraction of mutants at a given point in space and time obeys a linear response law of the type introduced in this paper. The theory may be used for evaluating the geographic position and the moment in time where and when a mutation originated.

    View details for DOI 10.1103/PhysRevE.65.061110

    View details for Web of Science ID 000176762500017

    View details for PubMedID 12188706

  • Y chromosome binary markers to study the high prevalence of males in Sardinian centenarians and the genetic structure of the Sardinian population HUMAN HEREDITY Passarino, G., Underhill, P. A., Cavalli-Sforza, L. L., Semino, O., Pes, G. M., Carru, C., Ferrucci, L., Bonafe, M., Franceschi, C., Deiana, L., Baggio, G., De Benedictis, G. 2001; 52 (3): 136-139

    Abstract

    We have analyzed a sample of 40 centenarians and 116 young controls from Sardinia, with a set of new Y chromosome binary markers, to evaluate if Y chromosome genes are involved in the high prevalence of males among centenarian Sardinians (1/2 vs. 1/4 in other populations studied). The results indicate that none of the seven lineages that account for >97% of the Y chromosome diversity in Sardinia provide an advantage with respect to the extreme longevity. However, our results, although based on the male-specific Y chromosome polymorphisms, give a clear profile of the pattern of genetic variability in Sardinia. Indeed they indicate that the Sardinian population had two main founder populations that have evolved in isolation for at least the last 5,000 years. These findings set the stage for future studies on longevity and other complex traits in Sardinia.

    View details for Web of Science ID 000171247900003

    View details for PubMedID 11588396

  • The Werner syndrome gene and global sequence variation GENOMICS Passarino, G., Shen, P., Van Kirk, J. B., Lin, A. A., De Benedictis, G., Sforza, L. L., Oefner, P. J., Underhill, P. A. 2001; 71 (1): 118-122

    Abstract

    We have identified a dense set of markers useful in association studies involving the Werner syndrome (WRN) gene. The homozygotic disruption of the WRN gene is the cause of Werner disease. In addition, this gene is likely to be involved in many complex traits, such as aging, or at least some of the traits and diseases related to age. To investigate the genetic variation associated with the WRN gene, a sample of 93 individuals representing all the continents was analyzed by denaturing high-performance liquid chromatography. A systematic survey of all 35 exons and flanking regions identified 58 single-nucleotide polymorphisms, 15 of which fall in the coding region and cause 11 missense mutations. The resulting global nucleotide diversity was 5.226 x 10(-4), with a slight difference between coding and noncoding regions.

    View details for Web of Science ID 000166515300012

    View details for PubMedID 11161804

  • Maori origins, Y-chromosome haplotypes and implications for human history in the Pacific HUMAN MUTATION Underhill, P. A., Passarino, G., Lin, A. A., Marzuki, S., Oefner, P. J., Cavalli-Sforza, L. L., Chambers, G. K. 2001; 17 (4): 271-280

    Abstract

    An assessment of 28 pertinent binary genetic markers on the non-recombining portion of the Y chromosome (NRY) in New Zealand Maori and other relevant populations has revealed a diverse genetic paternal heritage of extant Maori. A maximum parsimony phylogeny was constructed in which nine of the 25 possible binary haplotypes were observed. Although approximately 40% of the samples have haplotypes of unequivocal European origin, an equivalent number of samples have a single binary haplotype that is also observed in Indonesia and New Guinea, indicative of common indigenous Melanesian ancestry. The balance of the lineages has either typical East Asian signatures or alternative compositions consistent with their affinity to Melanesia or New Guinea. Molecular analysis of mtDNA variation confirms the presence of a single predominant characteristic Southeast Asian (9-bp deletion in the Region V) lineage. The Y-chromosome results support a pattern of complex interrelationships between Southeast Asia, Melanesia, and Polynesia, in contrast to mtDNA and linguistic data, which uphold a rapid and homogeneous Austronesian expansion. The Y-chromosome data highlight a distinctive gender-modulated pattern of differential gene flow in the history of Polynesia.

    View details for Web of Science ID 000167820300005

    View details for PubMedID 11295824

  • The phylogeography of Y chromosome binary haplotypes and the origins of modern human populations ANNALS OF HUMAN GENETICS Underhill, P. A., Passarino, G., Lin, A. A., Shen, P., Lahr, M. M., Foley, R. A., Oefner, P. J., Cavalli-Sforza, L. L. 2001; 65: 43-62

    Abstract

    Although molecular genetic evidence continues to accumulate that is consistent with a recent common African ancestry of modern humans, its ability to illuminate regional histories remains incomplete. A set of unique event polymorphisms associated with the non-recombining portion of the Y-chromosome (NRY) addresses this issue by providing evidence concerning successful migrations originating from Africa, which can be interpreted as subsequent colonizations, differentiations and migrations overlaid upon previous population ranges. A total of 205 markers identified by denaturing high performance liquid chromatography (DHPLC), together with 13 taken from the literature, were used to construct a parsimonious genealogy. Ancestral allelic states were deduced from orthologous great ape sequences. A total of 131 unique haplotypes were defined which trace the microevolutionary trajectory of global modern human genetic diversification. The genealogy provides a detailed phylogeographic portrait of contemporary global population structure that is emblematic of human origins, divergence and population history that is consistent with climatic, paleoanthropological and other genetic knowledge.

    View details for Web of Science ID 000168307900004

    View details for PubMedID 11415522

  • Y chromosome sequence variation and the history of human populations NATURE GENETICS Underhill, P. A., Shen, P. D., Lin, A. A., Jin, L., Passarino, G., Yang, W. H., Kauffman, E., Bonne-Tamir, B., Bertranpetit, J., Francalacci, P., Ibrahim, M., Jenkins, T., Kidd, J. R., Mehdi, S. Q., Seielstad, M. T., WELLS, R. S., Piazza, A., Davis, R. W., Feldman, M. W., Cavalli-Sforza, L. L., Oefner, P. J. 2000; 26 (3): 358-361

    Abstract

    Binary polymorphisms associated with the non-recombining region of the human Y chromosome (NRY) preserve the paternal genetic legacy of our species that has persisted to the present, permitting inference of human evolution, population affinity and demographic history. We used denaturing high-performance liquid chromatography (DHPLC; ref. 2) to identify 160 of the 166 bi-allelic and 1 tri-allelic site that formed a parsimonious genealogy of 116 haplotypes, several of which display distinct population affinities based on the analysis of 1062 globally representative individuals. A minority of contemporary East Africans and Khoisan represent the descendants of the most ancestral patrilineages of anatomically modern humans that left Africa between 35,000 and 89,000 years ago.

    View details for Web of Science ID 000165176500029

    View details for PubMedID 11062480

  • Population genetic implications from sequence variation in four Y chromosome genes PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Shen, P. D., Wang, F., Underhill, P. A., Franco, C., Yang, W. H., Roxas, A., Sung, R., Lin, A. A., Hyman, R. W., Vollrath, D., Davis, R. W., Cavalli-Sforza, L. L., Oefner, P. J. 2000; 97 (13): 7354-7359

    Abstract

    Some insight into human evolution has been gained from the sequencing of four Y chromosome genes. Primary genomic sequencing determined gene SMCY to be composed of 27 exons that comprise 4,620 bp of coding sequence. The unfinished sequencing of the 5' portion of gene UTY1 was completed by primer walking, and a total of 20 exons were found. By using denaturing HPLC, these two genes, as well as DBY and DFFRY, were screened for polymorphic sites in 53-72 representatives of the five continents. A total of 98 variants were found, yielding nucleotide diversity estimates of 2.45 x 10(-5), 5. 07 x 10(-5), and 8.54 x 10(-5) for the coding regions of SMCY, DFFRY, and UTY1, respectively, with no variant having been observed in DBY. In agreement with most autosomal genes, diversity estimates for the noncoding regions were about 2- to 3-fold higher and ranged from 9. 16 x 10(-5) to 14.2 x 10(-5) for the four genes. Analysis of the frequencies of derived alleles for all four genes showed that they more closely fit the expectation of a Luria-Delbrück distribution than a distribution expected under a constant population size model, providing evidence for exponential population growth. Pairwise nucleotide mismatch distributions date the occurrence of population expansion to approximately 28,000 years ago. This estimate is in accord with the spread of Aurignacian technology and the disappearance of the Neanderthals.

    View details for Web of Science ID 000087811600077

    View details for PubMedID 10861003

  • Distribution of haplotypes from a chromosome 21 region distinguishes multiple prehistoric human migrations Jin, L., Underhill, P. A., Doctor, V., Davis, R. W., Shen, P. D., Cavalli-Sforza, L. L., Oefner, P. J. NATL ACAD SCIENCES. 1999: 3796-3800

    Abstract

    Despite mounting genetic evidence implicating a recent origin of modern humans, the elucidation of early migratory gene-flow episodes remains incomplete. Geographic distribution of haplotypes may show traces of ancestral migrations. However, such evolutionary signatures can be erased easily by recombination and mutational perturbations. A 565-bp chromosome 21 region near the MX1 gene, which contains nine sites frequently polymorphic in human populations, has been found. It is unaffected by recombination and recurrent mutation and thus reflects only migratory history, genetic drift, and possibly selection. Geographic distribution of contemporary haplotypes implies distinctive prehistoric human migrations: one to Oceania, one to Asia and subsequently to America, and a third one predominantly to Europe. The findings with chromosome 21 are confirmed by independent evidence from a Y chromosome phylogeny. Loci of this type will help to decipher the evolutionary history of modern humans.

    View details for Web of Science ID 000079507900082

    View details for PubMedID 10097117

  • The Genetics of Human Populations. San Francisco: WH Freeman Mineola, NY: Dover Publications L.L. Cavalli-Sforza, W. Bodmer 1999
  • The Chinese Human Genome Diversity Project PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Cavalli-Sforza, L. L. 1998; 95 (20): 11501-11503

    View details for Web of Science ID 000076222200001

    View details for PubMedID 9751692

  • [Man and the diversity of his genome. An extraordinary phase in the history of population genetics]. Pathologie-biologie Cavalli-Sforza, L. 1998; 46 (2): 98-102

    Abstract

    Population genetics is almost eighty years old, but benefited only very recently from the advantages of direct DNA analysis. Nevertheless, much knowledge had already accumulated and was completely confirmed by the study of DNA markers. Major benefits of the latter came with microsatellites. It allowed to discover an error made with classical markers but even more seriously with RFLPs, because of the practically involuntary sampling of individuals almost exclusively of European origin for the detection of polymorphisms. Among other evolutionary application of microsatellites, the most attractive is their very recent use for dating population separations during the recent migration out of Africa of modern humans. They confirm the theory that this expansion was quite recent. Single nucleotide substitutions are the major material of evolution, and so far markers of this kind were rare. A new method, DHPLC, is excellent for their detection and testing. In humans it has been applied almost exclusively to the Y chromosome, and in a year it has given a completely new picture of Y chromosome genetics. Some applications of statistical methods to genetic geography of classical markers and ADN markers will show the power of the geographical approach, and therefore the need of a wide collection of population samples, as will be made possible by the HGDP (Human Genome Diversity Project).

    View details for PubMedID 9769919

  • The DNA revolution in population genetics TRENDS IN GENETICS Cavalli-Sforza, L. L. 1998; 14 (2): 60-65

    Abstract

    Unprecedental clarity has come to our understanding of genetic variation by the analysis of DNA sequences. It is not surprising that the new DNA technologies are leading to a resurgence of interest in population genetics. In this review, I discuss recent progress and future directions towards reconstructing the history of human populations. There is increasing consensus on a recent 'Out of Africa' origin of modern humans, which explains why the greatest fraction of genetic diversity is found within populations, rather than between them. The comparison of Y chromosome and mitochondrial DNA data shows remarkable sex differences in geographic variation. The analysis of Neanderthal DNA has been a major breakthrough in the study of fossil DNA. Among major hopes for the future are application to polygenic diseases.

    View details for Web of Science ID 000072252300007

    View details for PubMedID 9520599

  • Detection of numerous Y chromosome biallelic polymorphisms by denaturing high-performance liquid chromatography GENOME RESEARCH Underhill, P. A., Jin, L., Lin, A. A., Mehdi, S. Q., Jenkins, T., Vollrath, D., Davis, R. W., CAVALLISFORZA, L. L., Oefner, P. J. 1997; 7 (10): 996-1005

    Abstract

    Y chromosome haplotypes are particularly useful in deciphering human evolutionary history because they accentuate the effects of drift, migration, and range expansion. Significant acceleration of Y biallelic marker discovery and subsequent typing involving heteroduplex detection has been achieved by implementing an innovative and cost-efficient method called denaturing high-performance liquid chromatography (DHPLC). The power of the method resides in its sensitivity and ability to rapidly compare amplified sequences in an automated manner. We have determined the allelic states of 22 Y polymorphisms; 19 of which are unreported, in 718 diverse extant chromosomes; established haplotype frequencies; and deduced a phylogeny. All major geographic regions, including Eurasia, are characterized by mutations reflecting episodes of genetic drift and expansion. Most biallelic markers are localized regionally. However, some show wider dispersal and designate older, core haplotypes. One transversion defines a major haplogroup that distinguishes a previously unknown deep, apparently non-African branch. It provides evidence of an ancient bottleneck event. It is now possible to anticipate the inevitable detailed reconstruction of human Y chromosome genealogy based on several tens to even hundreds of these important polymorphisms.

    View details for Web of Science ID A1997YC51500009

    View details for PubMedID 9331370

  • Genes, peoples, and languages CAVALLISFORZA, L. L. NATL ACAD SCIENCES. 1997: 7719-7724

    Abstract

    The genetic history of a group of populations is usually analyzed by reconstructing a tree of their origins. Reliability of the reconstruction depends on the validity of the hypothesis that genetic differentiation of the populations is mostly due to population fissions followed by independent evolution. If necessary, adjustment for major population admixtures can be made. Dating the fissions requires comparisons with paleoanthropological and paleontological dates, which are few and uncertain. A method of absolute genetic dating recently introduced uses mutation rates as molecular clocks; it was applied to human evolution using microsatellites, which have a sufficiently high mutation rate. Results are comparable with those of other methods and agree with a recent expansion of modern humans from Africa. An alternative method of analysis, useful when there is adequate geographic coverage of regions, is the geographic study of frequencies of alleles or haplotypes. As in the case of trees, it is necessary to summarize data from many loci for conclusions to be acceptable. Results must be independent from the loci used. Multivariate analyses like principal components or multidimensional scaling reveal a number of hidden patterns and evaluate their relative importance. Most patterns found in the analysis of human living populations are likely to be consequences of demographic expansions, determined by technological developments affecting food availability, transportation, or military power. During such expansions, both genes and languages are spread to potentially vast areas. In principle, this tends to create a correlation between the respective evolutionary trees. The correlation is usually positive and often remarkably high. It can be decreased or hidden by phenomena of language replacement and also of gene replacement, usually partial, due to gene flow.

    View details for Web of Science ID A1997XM42800005

    View details for PubMedID 9223254

  • Autism and the X chromosome - Multipoint sib-pair analysis ARCHIVES OF GENERAL PSYCHIATRY Hallmayer, J., Hebert, J. M., Spiker, D., Lotspeich, L., McMahon, W. M., Petersen, P. B., Nicholas, P., Pingree, C., Lin, A. A., CAVALLISFORZA, L. L., Risch, N., CIARANELLO, R. D. 1996; 53 (11): 985-989

    Abstract

    Genetic factors undoubtedly play a major etiologic role in autism, but how it is inherited remains unanswered. The increased incidence in males suggests possible involvement of the X chromosome.Using data from 38 multiplex families with autism (2 or more autistic siblings), we performed a multipoint sib-pair linkage analysis between autism and 35 microsatellite markers located on the X chromosome. The model included a single parameter, the risk ratio lambda xs (i.e., ratio of risk to siblings compared with the population prevalence), owing to an X-linked gene. Different lambda xs values were assumed and regions of exclusion were established.The entire X chromosome could be excluded for a lambda xs value of 4. The ability to exclude an X-linked gene decreased with smaller lambda xs values, and some positive evidence was obtained with smaller values. A maximum lod score of 1.24 was obtained at locus DXS424 with a lambda xs value of 1.5.We were able to exclude any moderate to strong gene effect causing autism on the X chromosome. Smaller gene effects (lambda xs < 4) could not be excluded, in particular, a gene of small effect located between DXS453 and DXS1001.

    View details for Web of Science ID A1996VR82200002

    View details for PubMedID 8911221

  • Geographic clustering of human Y-chromosome haplotypes ANNALS OF HUMAN GENETICS Linares, A. R., Nayar, K., Goldstein, D. B., Hebert, J. M., Seielstad, M. T., Underhill, P. A., Lin, A. A., Feldman, M. W., Sforza, L. L. 1996; 60: 401-408

    Abstract

    Five polymorphic markers on the Y-chromosome (mostly microsatellites) were typed in 121 individuals from 13 populations around the world. With these markers 78 different haplotypes were detected. Haplotypes present more than once tend to be shared by individuals from the same population or continent. A reconstruction of haplotype phylogeny also indicates significant geographic structure in the data. Based on the similarity of the haplotypes, population relationships were examined and found to be largely concordant with those obtained with other markers. Even though the sample size and the number of markers are small, there is very signficant clustering of the haplotypes by continent of origin.

    View details for Web of Science ID A1996VT74200006

  • A pre-Columbian Y chromosome-specific transition and its implications for human evolutionary history PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Underhill, P. A., Jin, L., Zemans, R., Oefner, P. J., CAVALLISFORZA, L. L. 1996; 93 (1): 196-200

    Abstract

    A polymorphic C-->T transition located on the human Y chromosome was found by the systematic comparative sequencing of Y-specific sequence-tagged sites by denaturing high-performance liquid chromatography. The results of genotyping representative global indigenous populations indicate that the locus is polymorphic exclusively within the Western Hemisphere. The pre-Columbian T allele occurs at > 90% frequency within the native South and Central American populations examined, while its occurrence in North America is approximately 50%. Concomitant genotyping at the polymorphic tetranucleotide microsatellite DYS19 locus revealed that the C-->T mutation displayed significant linkage disequilibrium with the 186-bp allele. The data suggest a single origin of linguistically diverse native Americans with subsequent haplotype differentiation within radiating indigenous populations as well as post-Columbian European and African gene flow. The mutation may have originated either in North America at a very early time during the expansion or before it, in the ancestral population(s) from which all Americans may have originated. The analysis of linkage of the DYS199 and the DYS19 tetranucleotide loci suggests that the C-->T mutation may have occurred around 30,000 years ago. We estimate the nucleotide diversity over 4.2 kb of the nonrecombining portion of the Y chromosome to be 0.00014. compared to autosomes, the majority of variation is due to the smaller effective population size of the Y chromosome rather than selective sweeps. There begins to emerge a pattern of pronounced geographical localization of Y-specific nucleotide substitution polymorphisms.

    View details for Web of Science ID A1996TP36700039

    View details for PubMedID 8552603

  • GENETIC ABSOLUTE DATING BASED ON MICROSATELLITES AND THE ORIGIN OF MODERN HUMANS PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Goldstein, D. B., Linares, A. R., CAVALLISFORZA, L. L., Feldman, M. W. 1995; 92 (15): 6723-6727

    Abstract

    We introduce a new genetic distance for microsatellite loci, incorporating features of the stepwise mutation model, and test its performance on microsatellite polymorphisms in humans, chimpanzees, and gorillas. We find that it performs well in determining the relations among the primates, but less well than other distance measures (not based on the stepwise mutation model) in determining the relations among closely related human populations. However, the deepest split in the human phylogeny seems to be accurately reconstructed by the new distance and separates African and non-African populations. The new distance is independent of population size and therefore allows direct estimation of divergence times if the mutation rate is known. Based on 30 microsatellite polymorphisms and a recently reported average mutation rate of 5.6 x 10(-4) at 15 dinucleotide microsatellites, we estimate that the deepest split in the human phylogeny occurred about 156,000 years ago. Unlike most previous estimates, ours requires no external calibration of the rate of molecular evolution. We can use such calibrations, however, to test our estimate.

    View details for Web of Science ID A1995RJ89200012

    View details for PubMedID 7624310

  • DEMOGRAPHIC HISTORY OF INDIA AND MTDNA-SEQUENCE DIVERSITY AMERICAN JOURNAL OF HUMAN GENETICS Mountain, J. L., Hebert, J. M., Bhattacharyya, S., Underhill, P. A., Ottolenghi, C., Gadgil, M., CAVALLISFORZA, L. L. 1995; 56 (4): 979-992

    Abstract

    The demographic history of India was examined by comparing mtDNA sequences obtained from members of three culturally divergent Indian subpopulations (endogamous caste groups). While an inferred tree revealed some clustering according to caste affiliation, there was no clear separation into three genetically distinct groups along caste lines. Comparison of pairwise nucleotide difference distributions, however, did indicate a difference in growth patterns between two of the castes. The Brahmin population appears to have undergone either a rapid expansion or steady growth. The low-ranking Mukri caste, however, may have either maintained a roughly constant population size or undergone multiple bottlenecks during that period. Comparison of the Indian sequences to those obtained from other populations, using a tree, revealed that the Indian sequences, along with all other non-African samples, form a starlike cluster. This cluster may represent a major expansion, possibly originating in southern Asia, taking place at some point after modern humans initially left Africa.

    View details for Web of Science ID A1995QP66300020

    View details for PubMedID 7717409

  • AN EVALUATION OF GENETIC DISTANCES FOR USE WITH MICROSATELLITE LOCI GENETICS Goldstein, D. B., Linares, A. R., CAVALLISFORZA, L. L., Feldman, M. W. 1995; 139 (1): 463-471

    Abstract

    Mutations of alleles at microsatellite loci tend to result in alleles with repeat scores similar to those of the alleles from which they were derived. Therefore the difference in repeat score between alleles carries information about the amount of time that has passed since they shared a common ancestral allele. This information is ignored by genetic distances based on the infinite alleles model. Here we develop a genetic distance based on the stepwise mutation model that includes allelic repeat score. We adapt earlier treatments of the stepwise mutation model to show analytically that the expectation of this distance is a linear function of time. We then use computer simulations to evaluate the overall reliability of this distance and to compare it with allele sharing and Nei's distance. We find that no distance is uniformly superior for all purposes, but that for phylogenetic reconstruction of taxa that are sufficiently diverged, our new distance is preferable.

    View details for Web of Science ID A1995PZ24800040

    View details for PubMedID 7705647

  • COMPARISON OF 79 DNA POLYMORPHISMS TESTED IN AUSTRALIANS, JAPANESE AND PAPUA-NEW-GUINEANS WITH THOSE OF 5 OTHER HUMAN-POPULATIONS GENE GEOGRAPHY Lin, A. A., Hebert, J. M., Mountain, J. L., CAVALLISFORZA, L. L. 1994; 8 (3): 191-214

    Abstract

    Seventy-nine DNA polymorphisms from 57 loci (28 genes and 29 anonymous DNA segments) have been typed in eight human populations. Here we present allele frequencies for three populations (Japanese, New Guineans, and Australians) as well as revised frequencies for a Chinese sample: allele frequencies for five additional populations (Biaka and Mbuti Pygmies, Melanesians, Chinese, and Europeans) were described previously [Bowcock et al 1991a]. Evaluation of Hardy-Weinberg equilibrium for these polymorphisms suggested that the New Guinean sample may be from a highly substructured population. Average FST value for the 79 markers (polymorphisms) was 0.147 +/- 0.011 across the eight populations: Fst values for some markers changed dramatically with the addition of three populations--in particular, Australians and New Guineans. Average heterozygosity for eight populations was 0.307 +/- 0.014. Genetic distances indicated that the Australian sample may have some European ancestry. An average linkage tree inferred from these distances suggested that the first split of modern humans was between Africans and non-Africans, while the second major split was between Australians/New Guineans and all other non-Africans. The neighbor-joining tree also separated the African populations from all others. European polymorphism ascertainment bias and European admixture appear to have influenced both estimation of population heterozygosity and tree inference.

    View details for Web of Science ID A1994RE69600009

    View details for PubMedID 7662611

  • INFERENCE OF HUMAN-EVOLUTION THROUGH CLADISTIC-ANALYSIS OF NUCLEAR-DNA RESTRICTION POLYMORPHISMS PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Mountain, J. L., CAVALLISFORZA, L. L. 1994; 91 (14): 6515-6519

    Abstract

    Testing of nuclear DNA polymorphisms in human populations has been extended to closely related primates. For many polymorphisms, one allele is shared by two or more species: such shared alleles are likely to be ancestral and provide insight not only into the relationships among the primates but also into the evolutionary history of modern humans. Humans from among eight worldwide populations share an allele with chimpanzees for 62 out of 79 polymorphisms examined. Frequencies of these ancestral alleles strengthen the conclusion that the earliest major separation of modern humans was between Africans and non-Africans. The average time since mutation of the ancestral alleles producing the current set of polymorphisms is estimated to be 700,000 years. While differences among ancestral allele frequencies in human populations suggest that natural selection may have played a role in the evolution of a subset of these polymorphisms, simulations indicate that a European bias in the ascertainment of polymorphisms may be at least partially responsible for observed differences. Simulations also suggest that observed heterozygosity levels in African populations, for classical polymorphisms and restriction fragment length polymorphisms, are artificially low due to the same bias. Observed patterns of mean heterozygosity and mean ancestral allele frequency provide support for the hypothesis that Europeans and northeast Asians are closely related. This work suggests that polymorphisms should be selected by testing a random sample of extant humans.

    View details for Web of Science ID A1994NV42000057

    View details for PubMedID 7912828

  • The History and Geography of Human Genes Princeton: Princeton University Press. L.L. Cavalli-Sforza, P. Menozzi, A. Piazza 1994
  • SUBCLUSTERING OF HUMAN IMMUNOGLOBULIN-KAPPA LIGHT CHAIN VARIABLE REGION GENES GENOMICS Kurth, J. H., Mountain, J. L., CAVALLISFORZA, L. L. 1993; 16 (1): 69-77

    Abstract

    The human immunoglobulin kappa light chain (IgK) locus includes multiple variable region gene segments (Vk) that can be divided into four subgroups. Oligonucleotide primers were designed to amplify specifically gene segments of the VkI, VkII, and VkIII subgroups using the polymerase chain reaction (PCR). Product sequences were subcloned, sequenced, and compared. Phylogenetic analyses of sequences within each subgroup indicate that some subgroups can be subdivided further into "sub-subgroups." The history of Vk segment duplications apparently includes at least two separate periods, the first giving rise to the subgroups and the second generating further complexity within each subgroup. Duplications of large pieces of DNA (demonstrated by others through pulsed-field gel electrophoresis) also played a role. Rates of synonymous and non-synonymous base changes between pairs of sequences suggest that natural selection has played a major role in the evolution of the Vk variable gene segments, leading to sequence conservation in some regions and to increased diversity in others.

    View details for Web of Science ID A1993KW20500010

    View details for PubMedID 8486386

  • DEMIC EXPANSIONS AND HUMAN-EVOLUTION SCIENCE CAVALLISFORZA, L. L., Menozzi, P., Piazza, A. 1993; 259 (5095): 639-646

    Abstract

    Geographic expansions are caused by successful innovations, biological or cultural, that favor local growth and movement. They have had a powerful effect in determining the present patterns of human genetic geography. Modern human populations expanded rapidly across the Earth in the last 100,000 years. At the end of the Paleolithic (10,000 years ago) only a few islands and other areas were unoccupied. The number of inhabitants was then about one thousand times smaller than it is now. Population densities were low throughout the Paleolithic, and random genetic drift was therefore especially effective. Major genetic differences between living human groups must have evolved at that time. Population growths that began afterward, especially with the spread of agriculture, progressively reduced the drift in population and the resulting genetic differentiation. Genetic traces of the expansions that these growths determined are still recognizable.

    View details for Web of Science ID A1993KJ68800032

    View details for PubMedID 8430313

  • HUMAN GENOMIC DIVERSITY IN EUROPE - A SUMMARY OF RECENT RESEARCH AND PROSPECTS FOR THE FUTURE EUROPEAN JOURNAL OF HUMAN GENETICS CAVALLISFORZA, L. L., Piazza, A. 1993; 1 (1): 3-18

    Abstract

    Gene frequencies in Europe are intermediate with respect to those of other continents. A phylogenetic tree reconstructed from 95 gene frequencies tested on 26 European samples shows some deviant populations (Lapps, Sardinians, Greeks, Yugoslavs, Basques, Icelanders and Finns) and other weakly structured populations. This behavior may have a simple interpretation: Europeans have not evolved according to a tree of descent probably because of the major role played by migrations in prehistorical and historical times. The leading component of the European genetic landscape is a gradient that originates in the Middle East and is directed to the northwest. According to the hypothesis by Ammerman and Cavalli-Sforza this gradient was generated by a migration of Neolithic farmers from Anatolia followed by continuous, partial admixture of the expanding farmers with local hunter-gatherers. Other leading components of the gene frequencies in Europe show correlations with possible movements of Uralic-speaking people and pastoral nomads from a region north of the Caucasus and Black Sea, which according to Gimbutas is the area of origin of Indo-European speakers. This analysis is based on classical pre-DNA genetic markers. The prospect of future research using DNA polymorphisms is discussed in the context of the Human Genome Project.

    View details for Web of Science ID A1993MP05200002

    View details for PubMedID 7520820

  • 40 YEARS AGO IN GENETICS - THE UNORTHODOX MATING-BEHAVIOR OF BACTERIA GENETICS CAVALLISFORZA, L. L. 1992; 132 (3): 635-637

    View details for Web of Science ID A1992JV14400001

    View details for PubMedID 1468622

  • EVOLUTION OF MODERN HUMANS - EVIDENCE FROM NUCLEAR-DNA POLYMORPHISMS PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES Mountain, J. L., Lin, A. A., Bowcock, A. M., CAVALLISFORZA, L. L. 1992; 337 (1280): 159-165

    Abstract

    Previously we have described studies of the evolution of modern humans based upon data for classical genetic markers and for nuclear DNA polymorphisms. Such polymorphisms provide a different point of view regarding human evolution than do mitochondrial DNA sequences. Here we compare revised dates for major migrations of anatomically modern humans, estimated from archaeological data, with separations suggested by a genetic tree constructed from classical marker allele frequencies. Analyses of DNA polymorphisms have now been extended and compared with those of classical markers; genetic trees continue to support the hypothesis of an initial African and non-African divergence for modern humans. We have also begun testing non-human primates for a set of human DNA polymorphisms. For most polymorphisms tested so far, humans share a single allele with other primates; such shared alleles are likely to be ancestral. Populations living in humid tropical environments have significantly higher frequencies of ancestral alleles than do other populations, supporting the hypothesis that natural selection acts to maintain high frequencies of particular alleles in some environments.

    View details for Web of Science ID A1992JL98000006

    View details for PubMedID 1357690

  • COEVOLUTION OF GENES AND LANGUAGES REVISITED PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA CAVALLISFORZA, L. L., Minch, E., Mountain, J. L. 1992; 89 (12): 5620-5624

    Abstract

    In an earlier paper it was shown that linguistic families of languages spoken by a set of 38 populations associate rather strongly with an evolutionary tree of the same populations derived from genetic data. While the correlation was clearly high, there was no evaluation of statistical significance; no such test was available at the time. This gap has now been filled by adapting to this aim a procedure based on the consistency index, and the level of significance is found to be much stronger than 10(-3). Possible reasons for coevolution of strictly genetic characters and the strictly cultural linguistic system are discussed briefly. Results of this global analysis are compared with those obtained in independent local analysis.

    View details for Web of Science ID A1992HY05300086

    View details for PubMedID 1608971

  • EXCLUSION OF LINKAGE BETWEEN THE SEROTONIN-2 RECEPTOR AND SCHIZOPHRENIA IN A LARGE SWEDISH KINDRED ARCHIVES OF GENERAL PSYCHIATRY Hallmayer, J., Kennedy, J. L., Wetterberg, L., Sjogren, B., Kidd, K. K., CAVALLISFORZA, L. L. 1992; 49 (3): 216-219

    Abstract

    Family, twin, and adoption studies suggest that genetic factors play an important role in the etiology of schizophrenia. Detection of single gene(s) involved in a higher susceptibility to a hereditary disease is possible with linkage analysis. The effects of serotonin2-receptor antagonists on symptoms of schizophrenia suggest that a mutation in the gene coding for this receptor subtype might be involved in the pathophysiology of this disease. Recently a copy DNA encoding the serotonin 5-HT2 receptor has been isolated and with a human 5-HT2 receptor copy DNA probe the HTR2 locus has been mapped to chromosome 13. Using multipoint linkage analysis between schizophrenia and genetic markers spanning the region of the HTR2 locus, we were able to exclude linkage between this candidate gene and schizophrenia in a Swedish kindred. Given this result, we conclude that the serotonin 5-HT2 receptor gene itself is not a major susceptibility gene for schizophrenia in this family.

    View details for Web of Science ID A1992HG92500005

    View details for PubMedID 1348924

  • Study of an additional 58 DNA markers in five human populations from four continents. Gene geography Bowcock, A. M., Hebert, J. M., Mountain, J. L., Kidd, J. R., Rogers, J., Kidd, K. K., Cavalli-Sforza, L. L. 1991; 5 (3): 151-173

    Abstract

    One hundred DNA polymorphisms from 73 loci (42 genes and 31 anonymous DNA segments) were investigated in five populations (Biaka and Mbuti Pygmies, Melanesians, Chinese and Caucasoids). Data for 47 polymorphisms, including 42 of those discussed here, were described previously [Bowcock et al 1987]. Here we report statistical quantities of genetic importance for each gene and population. The average FST for the 100 markers is 0.137 and the average heterozygosity is 0.325. When known genes and anonymous segments are compared there is no significant difference in the average FST values or in the average heterozygosities.

    View details for PubMedID 1841601

  • Genes, peoples and languages. Scientific American Cavalli-Sforza, L. L. 1991; 265 (5): 104-110

    View details for PubMedID 1785035

  • A CONTIGUOUS LINKAGE MAP OF CHROMOSOME-13Q WITH 39 DISTINCT LOCI SEPARATED ON AVERAGE BY 5.1 CENTIMORGANS GENOMICS Bowcock, A. M., Farrer, L. A., Hebert, J. M., Bale, A. E., CAVALLISFORZA, L. 1991; 11 (3): 517-529

    Abstract

    A fine-structure linkage map of chromosome 13q is presented. This map contains 39 continuously linked loci defined by genotypes generated from the CEPH family DNAs with 56 probe and enzyme combinations. An alpha-satellite probe for sequences on chromosome 13 was included, resulting in a complete map of 13q with 39 distinct loci. The map spans 1.715 M in males and 2.099 M in females and the mean genetic distance between adjacent loci is 5.1 cM. Although there was generally a several-fold excess of female recombination in the interstitial portion of 13q, an excess of recombination in males was observed at both ends of this chromosomal arm. This map should be useful for the localization of any additional marker, gene, or disease locus of interest on chromosome 13q.

    View details for Web of Science ID A1991GK04600003

    View details for PubMedID 1685473

  • CALL FOR A WORLDWIDE SURVEY OF HUMAN GENETIC DIVERSITY - A VANISHING OPPORTUNITY FOR THE HUMAN GENOME PROJECT GENOMICS CAVALLISFORZA, L. L., Wilson, A. C., Cantor, C. R., COOKDEEGAN, R. M., KING, M. C. 1991; 11 (2): 490-491

    View details for Web of Science ID A1991GE39400042

    View details for PubMedID 1769670

  • NO LINKAGE BETWEEN D2 DOPAMINE RECEPTOR GENE REGION AND SCHIZOPHRENIA ARCHIVES OF GENERAL PSYCHIATRY Moises, H. W., Gelernter, J., Giuffra, L. A., Zarcone, V., Wetterberg, L., Civelli, O., Kidd, K. K., CAVALLISFORZA, L. L., Grandy, D. K., Kennedy, J. L., Vinogradov, S., Mauer, J., Litt, M., Sjogren, B. 1991; 48 (7): 643-647

    Abstract

    The dopamine hypothesis is one of the major etiological hypotheses of schizophrenia. The well-established role of genetic factors in schizophrenia together with reports of increased D2 dopamine receptor densities in untreated schizophrenic patients support the D2 dopamine receptor gene as a strong candidate gene for schizophrenia. The recent cloning of the D2 dopamine receptor gene made it possible to test the involvement of the D2 dopamine receptor locus (DRD2) in a large Swedish and a smaller Californian schizophrenia pedigree. Using multipoint linkage analysis between schizophrenia and a genetic map that includes the DRD2 locus and assuming a dominant mode of inheritance, we were able to exclude the DRD2 locus with a lod score of -4.14 for the penetrance of 0.72 and with a lod score of -3.05 for the lower bound penetrance of 0.56. The area of exclusion (lod score, less than -2.00) extended 27 centimorgans. These results provide strong evidence against linkage of the D2 dopamine receptor gene region to schizophrenia in the two pedigrees investigated. We conclude that the genetic predisposition to schizophrenia in these pedigrees is not due to aberrations in the DRD2 locus or the porphobilinogen deaminase locus. Our results do not support the D2 dopamine receptor hypothesis of schizophrenia. However, they cannot exclude the possibility that other genes regulating aspects of D2 dopamine expression might be involved in the etiology of schizophrenia, such as the expression of two D2 dopamine receptor subtypes by alternative RNA splicing.

    View details for Web of Science ID A1991FW28300008

    View details for PubMedID 2069495

  • KM TYPING WITH PCR - APPLICATION TO POPULATION SCREENING AMERICAN JOURNAL OF HUMAN GENETICS Kurth, J. H., Bowcock, A. M., Erlich, H. A., Nevo, S., CAVALLISFORZA, L. L. 1991; 48 (3): 613-620

    Abstract

    The immunoglobulin kappa light chain (IgK) locus may play a significant role in the pathology of both infectious and autoimmune diseases. Most of the work on IgK genetics has been conducted using immunological techniques for allelic typing and sequence analysis. This is restricted by availability of reagents and can be both expensive and time-consuming. PCR primers were designed to amplify the kappa constant gene (Ck), and four allele-specific oligonucleotides (ASOs) were used to distinguish the alleles in the amplified PCR products. Direct sequencing of PCR products was performed to confirm that the primers specifically amplified the Ck region and the ASOs differentiated the Km alleles. Sequencing of an average of 209 nucleotides of DNA from 50 individuals revealed no variation except at codon 191, which is known to be involved in a frequent polymorphism. An analysis of 347 different individual DNAs from 10 human populations was conducted to determine Km allelic frequencies within these populations and to apply this type of data collection to population studies.

    View details for Web of Science ID A1991FK47000022

    View details for PubMedID 1900145

  • DRIFT, ADMIXTURE, AND SELECTION IN HUMAN-EVOLUTION - A STUDY WITH DNA POLYMORPHISMS PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Bowcock, A. M., Kidd, J. R., Mountain, J. L., Hebert, J. M., Carotenuto, L., Kidd, K. K., CAVALLISFORZA, L. L. 1991; 88 (3): 839-843

    Abstract

    Accuracy of evolutionary analysis of populations within a species requires the testing of a large number of genetic polymorphisms belonging to many loci. We report here a reconstruction of human differentiation based on 100 DNA polymorphisms tested in five populations from four continents. The results agree with earlier conclusions based on other classes of genetic markers but reveal that Europeans do not fit a simple model of independently evolving populations with equal evolutionary rates. Evolutionary models involving early admixture are compatible with the data. Taking one such model into account, we examined through simulation whether random genetic drift alone might explain the variation among gene frequencies across populations and genes. A measure of variation among populations was calculated for each polymorphism, and its distribution for the 100 polymorphisms was compared with that expected for a drift-only hypothesis. At least two-thirds of the polymorphisms appear to be selectively neutral, but there are significant deviations at the two ends of the observed distribution of the measure of variation: a slight excess of polymorphisms with low variation and a greater excess with high variation. This indicates that a few DNA polymorphisms are affected by natural selection, rarely heterotic, and more often disruptive, while most are selectively neutral.

    View details for Web of Science ID A1991EW40000033

    View details for PubMedID 1992475

  • THE SEROTONIN RECEPTOR SUBTYPE-2 LOCUS HTR2 IS ON HUMAN CHROMOSOME-13 NEAR GENES FOR ESTERASE-D AND RETINOBLASTOMA-1 AND ON MOUSE CHROMOSOME-14 SOMATIC CELL AND MOLECULAR GENETICS Hsieh, C. L., Bowcock, A. M., Farrer, L. A., Hebert, J. M., Huang, K. N., CAVALLISFORZA, L. L., Julius, D., FRANCKE, U. 1990; 16 (6): 567-574

    Abstract

    Serotonin (5-hydroxytryptamine) functions as a neurotransmitter and a hormone. Its diverse actions are mediated by at least seven distinct cell surface receptor subtypes. The serotonin receptor subtype 2 (gene symbol HTR2) is a G-protein-coupled receptor, expressed primarily in the cerebral cortex, where upon stimulation it stimulates the hydrolysis of inositol phospholipids. We have mapped the HTR2 locus to human chromosome 13 and to mouse chromosome 14 by somatic cell hybrid analysis. Linkage studies in CEPH families, using a PvuII RFLP detected with the HTR2 probe, revealed tight linkage between HTR2 and ESD, the locus for esterase D. The most likely position for HTR2 is between ESD and RB1, the retinoblastoma-1 gene. The homologous loci in mouse, Rb-1 and Esd(Es-10) are on mouse chromosome 14, close to ag, agitans, a recessive neurological mutation. Having mapped Htr-2 to mouse chromosome 14, we predict that it falls into this known conserved gene cluster.

    View details for Web of Science ID A1990ER23200007

    View details for PubMedID 1980030

  • HOW CAN ONE STUDY INDIVIDUAL VARIATION FOR 3-BILLION NUCLEOTIDES OF THE HUMAN GENOME AMERICAN JOURNAL OF HUMAN GENETICS CAVALLISFORZA, L. L. 1990; 46 (4): 649-651

    View details for Web of Science ID A1990CW54900003

    View details for PubMedID 2316518

  • SPATIAL SUBDIVISION OF POPULATIONS AND ESTIMATES OF GENETIC-VARIATION THEORETICAL POPULATION BIOLOGY CAVALLISFORZA, L. L., Feldman, M. W. 1990; 37 (1): 3-25

    Abstract

    Measures of variation in space are strongly affected by correlations between subdivisions used for sampling. Here we consider variation in gene frequencies across populations. Usually the variance of gene frequencies is standardized by dividing it by the mean gene frequency times one minus the mean (FST). Under the model of isolation by distance (usually called the "stepping stone" model), at the stationary state the correlation between the gene frequencies of two populations falls exponentially with the geographic distance between them. Using this model, we derive formulas for variances of blocks of populations of different sizes in one- and two-dimensional space and suggest that the theoretical results may be useful for understanding real observations, some examples of which are presented. We demonstrate how FST increases with the degree of subdivision among populations. We also show the effect of gaps between the sampled populations. Our results are valid, however, for traits other than gene frequencies, as long as their correlation with geographic distance falls exponentially. In the extension to 2-dimensional spaces, we present in closed form the distributions of distances between nodes of a lattice or of two lattices. These distributions might have applications in ecology.

    View details for Web of Science ID A1990CU08800001

    View details for PubMedID 2326767

  • CULTURAL TRANSMISSION AND NUTRITION CAVALLISFORZA, L. L. KARGER. 1990: 35-48

    View details for Web of Science ID A1990BR21U00004

    View details for PubMedID 2197805

  • T-CELL RECEPTOR V-ALPHA AND C-ALPHA ALLELES ASSOCIATED WITH MULTIPLE-SCLEROSIS AND MYASTHENIA-GRAVIS PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Oksenberg, J. R., Sherritt, M., Begovich, A. B., Erlich, H. A., Bernard, C. C., CAVALLISFORZA, L. L., Steinman, L. 1989; 86 (3): 988-992

    Abstract

    Polymorphic markers in genes encoding that alpha chain of the human T-cell receptor (TcR) have been detected by Southern blot analysis in Pss I digests. Polymorphic bands were observed at 6.3 and 2.0 kilobases (kb) with frequencies of 0.30 and 0.44, respectively, in the general population. Using the polymerase chain reaction (PCR) method, we amplified selected sequences derived from the full-length TcR alpha cDNA probe. These PCR products were used as specific probes to demonstrate that the 6.3-kb polymorphic fragment hybridizes to the variable (V)-region probe and the 2.0-kb fragment hybridizes to the constant (C)-region probe. Segregation of the polymorphic bands was analyzed in family studies. To look for associations between these markers and autoimmune diseases, we have studied the restriction fragment length polymorphism distribution of the Pss I markers in patients with multiple sclerosis, myasthenia gravis, and Graves disease. Significant differences in the frequency of the polymorphic V alpha and C alpha markers were identified between patients and healthy individuals.

    View details for Web of Science ID A1989T144400049

    View details for PubMedID 2915992

  • RECONSTRUCTION OF HUMAN-EVOLUTION - BRINGING TOGETHER GENETIC, ARCHAEOLOGICAL, AND LINGUISTIC DATA PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA CAVALLISFORZA, L. L., Piazza, A., Menozzi, P., Mountain, J. 1988; 85 (16): 6002-6006

    Abstract

    The genetic information for this work came from a very large collection of gene frequencies for "classical" (non-DNA) polymorphisms of the world aborigines. The data were grouped in 42 populations studied for 120 alleles. The reconstruction of human evolutionary history thus generated was checked with statistical techniques such as "boot-strapping". It changes some earlier conclusions and is in agreement with more recent ones, including published and unpublished DNA-marker results. The first split in the phylogenetic tree separates Africans from non-Africans, and the second separates two major clusters, one corresponding to Caucasoids, East Asians, Arctic populations, and American natives, and the other to Southeast Asians (mainland and insular), Pacific islanders, and New Guineans and Australians. Average genetic distances between the most important clusters are proportional to archaeological separation times. Linguistic families correspond to groups of populations with very few, easily understood overlaps, and their origin can be given a time frame. Linguistic superfamilies show remarkable correspondence with the two major clusters, indicating considerable parallelism between genetic and linguistic evolution. The latest step in language development may have been an important factor determining the rapid expansion that followed the appearance of modern humans and the demise of Neanderthals.

    View details for Web of Science ID A1988P781800050

    View details for PubMedID 3166138

  • The human "interferon-beta 2/hepatocyte stimulating factor/interleukin-6" gene: DNA polymorphism studies and localization to chromosome 7p21. Genomics Bowcock, A. M., Kidd, J. R., Lathrop, G. M., DANESHVAR, L., May, L. T., Ray, A., Sehgal, P. B., Kidd, K. K., Cavalli-Sforza, L. L. 1988; 3 (1): 8-16

    Abstract

    The human interferon-beta 2 gene (IFNB2) product is identical to that for the B-cell stimulation factor-2 (BSF-2), the hybridoma growth factor (HGF) ("interleukin-6"), and the hepatocyte stimulating factor (HSF). Proteins derived from this gene mediate the plasma protein response to tissue injury (acute-phase response) and regulate the growth and differentiation of both B and T cells. By using the enzymes MspI, BstNI, and BglI, three polymorphic systems were detected with probes for the IFNB2 gene. The MspI and BglI polymorphisms are likely to be due to base pair substitutions; the BstNI polymorphism was revealed by nine other enzymes and is likely to be due to DNA insertions within 1 kb of the 3' flanking region of the gene. This region is rich in AT dinucleotides, and slippage at DNA replication may generate the insertions of between 0.07 and 0.23 kb that were observed. The polymorphic MspI site also lies within the vicinity of the fifth exon. The BglI polymorphic site is likely to lie in 5' flanking DNA. The three polymorphisms are separate, and a variety of haplotypes was observed. A low level of linkage disequilibrium exists between the MspI and the BglI alleles. MspI and BstNI polymorphisms were observed in Caucasoids, CAR Pygmies, Zaire Pygmies, Melanesians, and Chinese but at differing frequencies, and not all alleles were present in all populations. The BglI polymorphism was observed in Caucasoids and Africans only. Linkage studies involving the IFNB2 gene and 27 other chromosome 7 markers have localized it to between D7S135 and D7S370 at 7p22-p21.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for PubMedID 2906047

  • POLYMORPHIC MARKERS OF HUMAN T-CELL RECEPTOR ALPHA-GENES AND BETA-GENES - FAMILY STUDIES AND COMPARISON OF FREQUENCIES IN HEALTHY-INDIVIDUALS AND PATIENTS WITH MULTIPLE-SCLEROSIS AND MYASTHENIA-GRAVIS HUMAN IMMUNOLOGY Oksenberg, J. R., GAISER, C. N., CAVALLISFORZA, L. L., Steinman, L. 1988; 22 (2): 111-121

    Abstract

    Polymorphic markers for the human T-cell receptor (TcR) genes are described. With a TcR beta-chain probe, polymorphic allelic fragments of 5.4 and 1.8 kb were detected in KpnI digests, and fragments of 12.5 and 11.5 kb were seen in the BglII digests. Polymorphism in alpha chain genes was observed in TaqI-digested DNA samples with bands at 10.2 and 6.2-2.1 kb. Mendelian codominant inheritance for all three polymorphisms was confirmed in family studies. The gene frequencies for these alleles were determined in a sample of 70 normal unrelated Caucasian individuals, and were shown to be in Hardy-Weinberg equilibrium. There were no significant differences in the frequency of these polymorphic alpha and beta alleles between patients with multiple sclerosis and patients with myasthenia gravis as compared to a panel of control healthy individuals.

    View details for Web of Science ID A1988P107200004

    View details for PubMedID 2971027

  • HIGH RECOMBINATION BETWEEN 2 PHYSICALLY CLOSE HUMAN BASEMENT-MEMBRANE COLLAGEN GENES AT THE DISTAL END OF CHROMOSOME-13Q PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Bowcock, A. M., Hebert, J. M., Wijsman, E., Gadi, I., CAVALLISFORZA, L. L., BOYD, C. D. 1988; 85 (8): 2701-2705

    Abstract

    Two basement membrane collagen genes coding for the pro alpha 1 chain and pro alpha 2 chain of type IV collagen map to 13q34 and are linked with a maximum likelihood estimate of recombination of 0.028 at a logarithm of odds (lod) score of 19.98. The single-copy sequence that identifies the locus D13S3 is also closely linked to both collagen genes. Four enzymes reveal polymorphisms with COL4A1, and 10 haplotypes have been observed in Caucasoids. Within COL4A1 a nonrandom association of alleles exists only between alleles defined by Hae III and those defined by the other three enzymes. A random association of alleles of COL4A1 and COL4A2 is observed. Between the two collagen genes were detected three meiotic recombination events that contributed to the estimate of 2.8% recombination. This is higher than expected for two genes that lie within 650 kilobases of each other. The lack of linkage disequilibrium between COL4A1 and COL4A2 is in agreement with the relatively high recombination that is observed.

    View details for Web of Science ID A1988N023400060

    View details for PubMedID 2895928

  • POLYMORPHISMS REVEALED BY RANDOM PROBE H2-10 [D13S26] WHICH MAPS TO CHROMOSOME 13Q21-Q22 NUCLEIC ACIDS RESEARCH Bowcock, A. M., Hebert, J. M., CAVALLISFORZA, L. L. 1988; 16 (6): 2745-2745

    View details for Web of Science ID A1988M765000049

    View details for PubMedID 2896341

  • Study of 47 DNA markers in five populations from four continents. Gene geography Bowcock, A. M., Bucci, C., Hebert, J. M., Kidd, J. R., Kidd, K. K., Friedlaender, J. S., Cavalli-Sforza, L. L. 1987; 1 (1): 47-64

    Abstract

    Forty seven DNA markers from 30 genes or chromosomal regions were investigated in five populations (Biaka and Mbuti Pygmies, Melanesians, Chinese and Caucasoids). Both the variation between populations (measured by FST) and between markers is highly significant. The average heterozygosity for all markers is .284 and the average FST is .145. There was no significant difference in the FST values, or in the average heterozygosity between known genes and random segments. The FST distance between all populations considered in pairs, and averaged over all loci favours a primary split between Eurasia and Africa, but this conclusion is neither statistically significant nor uncomplicated. Condensing the 47 markers into 30 "genes" where 10 were treated as haplotypes, it was found that the haplotypes always give higher FST's than the separate markers, although similar conclusions can be drawn.

    View details for PubMedID 2908691

  • THE PRO ALPHA-1 (IV) COLLAGEN GENE IS LINKED TO THE D13S3 LOCUS AT THE DISTAL END OF HUMAN-CHROMOSOME 13Q CYTOGENETICS AND CELL GENETICS Bowcock, A. M., Hebert, J. M., Christiano, A. M., Wijsman, E., CAVALLISFORZA, L. L., BOYD, C. D. 1987; 45 (3-4): 234-236

    View details for Web of Science ID A1987L645000018

    View details for PubMedID 2891465

  • A SYSTEMATIC-APPROACH FOR DETECTING HIGH-FREQUENCY RESTRICTION FRAGMENT LENGTH POLYMORPHISMS USING LARGE GENOMIC PROBES AMERICAN JOURNAL OF HUMAN GENETICS Feder, J., Yen, L., Wijsman, E., Wang, L., Wilkins, L., Schroder, J., Spurr, N., Cann, H., Blumenberg, M., CAVALLISFORZA, L. L. 1985; 37 (4): 635-649

    Abstract

    Thirteen phage clones containing low-copy sequences were isolated from a human DNA library and tested for their ability to detect restriction fragment length polymorphisms (RFLPs). Reported are the RFLPs revealed with each clone, all found in frequencies useful for linkage studies. Cytological data are available for five of the 13 clones, with regional assignments made for three of the markers by in situ hybridization. It is concluded that phage clones containing large unique DNA inserts detect multiple RFLPs with high efficiency. An analysis of the relative efficiency of 20 restriction enzymes for detecting single nucleotide changes is discussed by comparing the observed data to those expected on the basis of recognition and potential site frequencies, as computed from the dinucleotide distribution. Finally, in an effort to facilitate linkage studies using polymorphic DNA sequences, experiments were made with pools of probes from various sources.

    View details for Web of Science ID A1985APR1800002

    View details for PubMedID 9556655

  • The Neolithic Transition and the Genetics of Populations in Europe Princeton: Princeton University Press L.L. Cavalli-Sforza, A. Ammerman 1984
  • Cultural Transmission and Evolution Princeton: Princeton University Press. L.L. Cavalli-Sforza, M. Feldman 1981
  • ETHNIC VARIATION IN GENETIC DISEASE - POSSIBLE ROLES OF HITCHHIKING AND EPISTASIS AMERICAN JOURNAL OF HUMAN GENETICS Wagener, D. K., CAVALISFORZA, L. L. 1975; 27 (3): 348-364

    Abstract

    The high incidence of some genetic diseases in certain ethnic groups is important in planning of medical genetic programs. Simple interaction models predict that at least some lethal recessive alleles will have "hitchhiked" to increased frequencies because of linkage to genes whose alleles have been favored by selection for other reasons in certain populations. In the absence of linkage or epistasis with a gene favored by selection, heterozygote advantage for a recessive lethal may produce the same phenomenon. In the hitchhiking model (linkage), the increase in the gene frequency is temporary, but the length of time that the increased gene frequency is at least double the base frequency may be quite long. Changes in gene frequency for the unlinked epistatic model result in a new equilibrium with a possibly higher gene frequency. The most likely chromosomal regions in which hitchhiked lethal recessives would be found are in the vicinity of genes whose allelic frequencies vary substantially among human racial groups (e.g., Gm, Rh, Duffy, lactose tolerance, or HL-A). There will be a hitchhiking effect if recombination distance is less than the selective advantage. The closer the linkage of two loci, the easier hitchhiking effects will be to detect. Hitchhiking is suggested by nonrandom association of the recessive disease and one of the selected markers, as in the case of Gm and cystic fibrosis. However, there is so far insufficient evidence of linkage between them. More pedigree information is necessary than is now available.

    View details for Web of Science ID A1975AD23600010

    View details for PubMedID 803016