History Of Human Genetics Research Articles

Neolithic to Bronze Age human maternal genetic history in Yunnan, China

Yunnan in southwest China is a geographically and ethnically complex region at the intersection of southern China and Southeast Asia, and a focal point for human migrations. To clarify its maternal genetic history, we generated 152 complete mitogenomes from 17 Yunnan archaeological sites. Our results reveal distinct genetic histories segregated by geographical regions. Maternal lineages of ancient populations from northwestern and northern Yunnan exhibit closer affinities with past and present-day populations from northern East Asia and Tibet, providing important genetic evidence for the migration and interaction of populations along the Tibetan-Yi corridor since the Neolithic. Between 5500 and 1800 years ago, central Yunnan populations maintained their internal genetic relationships, including a 7000-year-old basal lineage of the rare and widely dispersed haplogroup M61. At the Xingyi site, changes in mitochondrial DNA haplogroup occurred between the Late Neolithic and Bronze Age, with haplogroup shifting from those predominant in the Yellow River region to those predominant in coastal southern China. These results highlight the high diversity of Yunnan populations during the Neolithic to Bronze Age.

A geographic history of human genetic ancestry.

Describing the distribution of genetic variation across individuals is a fundamental goal of population genetics. In humans, traditional approaches for describing population genetic variation often rely on discrete genetic ancestry labels, which, despite their utility, can obscure the complex, multi-faceted nature of human genetic history. These labels risk oversimplifying ancestry by ignoring its temporal depth and geographic continuity, and may therefore conflate notions of race, ethnicity, geography, and genetic ancestry. Here, we present a method that capitalizes on the rich genealogical information encoded in genomic tree sequences to infer the geographic locations of the shared ancestors of a sample of sequenced individuals. We use this method to infer the geographic history of genetic ancestry of a set of human genomes sampled from Europe, Asia, and Africa, accurately recovering major population movements on those continents. Our findings demonstrate the importance of defining the spatial-temporal context of genetic ancestry to describing human genetic variation and caution against the oversimplified interpretations of genetic data prevalent in contemporary discussions of race and ancestry.

More evidence for widespread antagonistic pleiotropy in polymorphic disease alleles.

Many loci segregate alleles classified as "genetic diseases" due to their deleterious effects on health. However, some disease alleles have been reported to show beneficial effects under certain conditions or in certain populations. The beneficial effects of these antagonistically pleiotropic alleles may explain their continued prevalence, but the degree to which antagonistic pleiotropy is common or rare is unresolved. We surveyed the medical literature to identify examples of antagonistic pleiotropy to help determine whether antagonistic pleiotropy appears to be rare or common. We identified ten examples of loci with polymorphisms for which the presence of antagonistic pleiotropy is well supported by detailed genetic or epidemiological information in humans. One additional locus was identified for which the supporting evidence comes from animal studies. These examples complement over 20 others reported in other reviews. The existence of more than 30 identified antagonistically pleiotropic human disease alleles suggests that this phenomenon may be widespread. This poses important implications for both our understanding of human evolutionary genetics and our approaches to clinical treatment and disease prevention, especially therapies based on genetic modification.

Human genetic history on the Tibetan Plateau in the past 5100 years

Using genome-wide data of 89 ancient individuals dated to 5100 to 100 years before the present (B.P.) from 29 sites across the Tibetan Plateau, we found plateau-specific ancestry across plateau populations, with substantial genetic structure indicating high differentiation before 2500 B.P. Northeastern plateau populations rapidly showed admixture associated with millet farmers by 4700 B.P. in the Gonghe Basin. High genetic similarity on the southern and southwestern plateau showed population expansion along the Yarlung Tsangpo River since 3400 years ago. Central and southeastern plateau populations revealed extensive genetic admixture within the plateau historically, with substantial ancestry related to that found in southern and southwestern plateau populations. Over the past ~700 years, substantial gene flow from lowland East Asia further shaped the genetic landscape of present-day plateau populations. The high-altitude adaptive EPAS1 allele was found in plateau populations as early as in a 5100-year-old individual and showed a sharp increase over the past 2800 years.

The racist origins, racialist connotations, and purity assumptions of the concept of "admixture" in human evolutionary genetics.

The concept of admixture is currently widely being used, both in population genetics research and in DNA ancestry testing discourse. It is assumed to describe the process of gene flow between 2 previously distinct populations that eventually become admixed because of this flow. The concept per se does not require pure or unadmixed populations; the changes are relative and what matters is the level of admixture before and after the event under consideration. However, in this paper, we argue that the concept of admixture as currently used assumes the existence of pure or unadmixed categories. These do not need to have actually existed but to be able to exist in principle. We argue that this is a problematic notion that accrues from the racialist origins of the term admixture, which, as a result, is based on assumptions about purity. We suggest that scientists should be very cautious in their use of this term, especially in science education and communication. We also suggest that the term admixture should be better replaced by terms denoting similarity rather than difference.

Heredity under the Microscope: Chromosomes and the Study of the Human Genome by Soraya de Chadarevian (review).

Reviewed by: Heredity under the Microscope: Chromosomes and the Study of the Human Genome by Soraya de Chadarevian Miguel García-Sancho Soraya de Chadarevian. Heredity under the Microscope: Chromosomes and the Study of the Human Genome. Chicago: University of Chicago Press, 2020. 272 pp. Ill. $37.50 (978-0-226-68511-3). In Heredity under the Microscope, Soraya de Chadarevian complements the picture of post-World War II biomedicine that she uncovered in her previous book, Designs for Life: Molecular Biology after World War II.1 Unlike in her earlier monograph, here she focuses on chromosomes as spaces of convergence of several lines of inquiry. This focus on research objects rather than disciplinary developments leads her to investigate a variety of practices that life scientists deployed to visualize and [End Page 466] interpret human chromosomes. The diversity of disciplinary backgrounds of these scientists and the multiplicity of uses to which their chromosome practices were put enable the author to expand the historiographical boundaries of both molecular biology and genetics research. Firstly, de Chadarevian disentangles “the study of postwar human heredity from the predominant concern about continuities with eugenic practices” (p. 5). The book does not limit itself to documenting the invention of karyotyping techniques to represent and detect anomalies in human chromosomes; it follows their standardization and spread, including their use as evidence of safe levels of radiation in the workplace (chapter 1) or sex assignment in the Olympic games (chapter 3). The emphasis on these uses, departed as they were from scientific theories about population improvement, displaces eugenics as the dominant interpretative framework of the history of human genetics. Secondly, the book presents chromosomes as showing “historical commonalities” (p. 177) between two approaches that have been traditionally considered as separate: molecular genetics and microscope-assisted chromosome observations. De Chadarevian stresses how these two approaches emerged as a consequence of the key role that nuclear research had played during World War II and the search of peacetime applications. Radioactive isotopes decisively fostered molecular biology, while the investigation of the effects of radiation was a crucial concern of human and medical geneticists using chromosome observations (chapter 1). Both molecular biologists and chromosome researchers also attempted to apply computers to their investigations, the former as an aid to the structural study of proteins and DNA, and the latter to automate the interpretation of karyotype images (chapter 4). However, whereas molecular biologists focused on simpler organisms, chromosome researchers engaged with both human populations and patients in the clinic. Radiation-induced leukemia was their first focus for then rapidly shifting to other conditions (especially those affecting mental abilities and sex identity) and larger-scale epidemiological studies (chapters 2 and 4). The 1960s, a decade that historians have dubbed the golden age of molecular biology,2 was also a time of expansion of chromosome observations. From the mid-1970s onward, molecular biologists turned to human subjects in order to realize the medical promise of the new recombinant DNA techniques. It is at this point when the intersection with chromosome research becomes more visible and de Chadarevian wonders “whose turn” this represents in history, a molecularization of human genetics or a humanization of molecular biology (pp. 171–76). Although subsequent success stories have put the emphasis on molecular biology, chapter 5 shows the importance of chromosome research as a key tool for gene mapping and the emergence of the human genome as an object of study. Even in the so-called post-genomic era, chromosome observations are [End Page 467] essential to clinically interpret the molecular sequence data derived from the Human Genome Project. Overall, the book offers a most welcomed framework to address the coexistence of chromosome observations and molecular biology, and their importance in genomics research. Understanding this is a pressing historiographical problem, given the dominance of molecular biologists in existing narratives and the apparent revival of chromosome research. There is yet still work to do in exploring specific overlaps between the visual and molecular approaches to the genome. A potential candidate is Victor McKusick, a main actor in de Chadarevian’s account and a co-author of the article in which Celera Genomics presented one of the draft sequences of the human...

New Meanings in the Archive: Privacy, Technological Change and the Status of Sources.

This essay reflects on how technological changes in biomedicine can affect what archival sources are available for historical research. Historians and anthropologists have examined the ways in which old biomedical samples can be made to serve novel scientific purposes, such as when decades‐old frozen tissue specimens are analyzed using new genomic techniques. Those uses are also affected by shifting ethical regimes, which affect who can do what with old samples, or whether anything can be done with them at all. Archival collections are subject to similar dynamics, as institutional change and shifts in ethical guidelines and privacy laws affect which sources can be accessed and which are closed. I witnessed just such a change during my research into human genetics using archives in the Wellcome Collection. A few years into my project, those archives had their privacy conditions reassessed, and I saw how some sources previously seen as neutral were now understood to contain personal sensitive information. This paper describes the conditions of this shift—including the effects of technological change, new ethical considerations, and changing laws around privacy. I reflect on how these affected my understanding of the history of human genetics, and how I and others might narrate it.

The False Dawn of Polygenic Risk Scores for Human Disease Prediction.

Polygenic risk scores (PRSs) are being constructed for many diseases and are presented today as a promising avenue in the field of human genetics. These scores aim at predicting the risk of developing a disease by leveraging the many genome-wide association studies (GWAS) conducted during the two last decades. Important investments are being made to improve score estimates by increasing GWAS sample sizes, by developing more sophisticated methods, and by proposing different corrections for potential biases. PRSs have entered the market with direct-to-consumer companies proposing to compute them from saliva samples and even recently to help parents select the healthiest embryos. In this paper, we recall how PRSs arose and question the credit they are given by revisiting underlying assumptions in light of the history of human genetics and by comparing them with estimated breeding values (EBVs) used for selection in livestock.

How Neanderthals Became White: The Introgression of Race into Contemporary Human Evolutionary Genetics.

AbstractHuman evolutionary theory has a history rife with racial biases in what might be considered its distant past that can appear glaringly obvious from our current vantage point. Despite the recognition that as a social activity science is always vulnerable to such biases (and science that attempts to uncover human origin stories all the more so), commitment to the scientific method can lead us to believe that we have improved on, overcome, or otherwise escaped these tendencies in our contemporary practices, whether through scientific contrition, changing social context, or better training and composition of research teams or as a result of advances in technologies and methodologies. This article adapts the evolutionary biology concept of introgression, which refers to the hybridization and repeated bidirectional backcross exchange of information between species, as a metaphorical frame to examine science itself and to trace the ways in which historic race biases from earlier, disowned human evolution research have been retained and selected for beneath the surface of current genomic research today. It takes as its focus the sequencing of the Neanderthal genome, first announced in 2006 and refined since, and the explosion of scientific research comparing that sequence to present-day human DNA from individuals around the world to illustrate the ways in which current research questions and findings in comparative evolutionary genomics draw on and dredge up earlier biases, albeit adapted to and disguised within contemporary social relations and power differentials.

A genetic history of migration, diversification, and admixture in Asia

L.L. Cavalli-Sforza spearheaded early efforts to study the genetic history of humans, recognizing the importance of sampling diverse populations worldwide. He supported research on human evolutionary genetics in Asia, with research on human dispersal into Asia and genetic distances between present-day East Asians in the late 20th century. Since then, great strides have been made in understanding the genetic history of humans in Asia, through large-scale genomic sequencing of present-day humans and targeted sequencing of DNA from ancient humans. In this review, I survey the genetic prehistory of humans in Asia, based on research using sequence data from humans who lived in Asia as early as 45,000 years ago. Genetic studies comparing present-day Australasians and Asians show that they likely derived from a single dispersal out of Africa, rapidly differentiating into three main lineages: one that persists partially in South Asia, one that is primarily found today in Australasia, and one that is widely represented across Siberia, East Asia, and Southeast Asia. Studies of ancient DNA from human remains in Asia dating from as far back as 45,000 years has greatly increased our understanding of the population dynamics leading to the current Asian populations. Based on "Jin L, Underhill PA, Doctor V, Davis RW, Shen P, Cavalli-Sforza LL, Oefner PJ. Distribution of haplotypes from a chromosome 21 region distinguishes multiple prehistoric human migrations. Proc Natl Acad Sci U S A. 1999;96(7):3796-3800”.

Insights into human history from the first decade of ancient human genomics

Recent advancements in DNA sequencing technologies and laboratory preparation protocols have rapidly expanded the scope of ancient DNA research over the past decade, both temporally and geographically. Discoveries include interactions between archaic and modern humans as well as modern human population dynamics, including those coinciding with the Last Glacial Maximum and the settlement history of most world regions. This new type of data allows us to examine the deep past of human population dynamics and sharpen the current understanding of our present. The continued development in the ancient DNA field has transformed our understanding of human genetic history and will keep uncovering the further mysteries of our recent evolutionary past.

Oral history of German human genetics: historical research methods for collecting and processing narrative interviews

Between 2016 and 2018, interviews with 33 persons were conducted about the history of human genetics in Germany between 1970 and the 2000s. 29 interviewees gave consent to have the interviews used for historical research. These interviews are currently being analysed with the methods of qualitative content analysis and grounded theory. The focus of this article lies on the critical examination of the method of oral history and its application to human genetics. The oral history project focuses on questions regarding (1) biographical data and careers of interviewees, (2) development and application of diagnostic and therapeutic techniques, (3) establishment and growth of institutions of human genetics and (4) social debates regarding the discipline.

Reconstructing the Human Genetic History of Mainland Southeast Asia: Insights from Genome-Wide Data from Thailand and Laos

Thailand and Laos, located in the center of Mainland Southeast Asia (MSEA), harbor diverse ethnolinguistic groups encompassing all five language families of MSEA: Tai-Kadai (TK), Austroasiatic (AA), Sino-Tibetan (ST), Hmong-Mien (HM), and Austronesian (AN). Previous genetic studies of Thai/Lao populations have focused almost exclusively on uniparental markers and there is a paucity of genome-wide studies. We therefore generated genome-wide SNP data for 33 ethnolinguistic groups, belonging to the five MSEA language families from Thailand and Laos, and analyzed these together with data from modern Asian populations and SEA ancient samples. Overall, we find genetic structure according to language family, albeit with heterogeneity in the AA-, HM-, and ST-speaking groups, and in the hill tribes, that reflects both population interactions and genetic drift. For the TK speaking groups, we find localized genetic structure that is driven by different levels of interaction with other groups in the same geographic region. Several Thai groups exhibit admixture from South Asia, which we date to ∼600–1000 years ago, corresponding to a time of intensive international trade networks that had a major cultural impact on Thailand. An AN group from Southern Thailand shows both South Asian admixture as well as overall affinities with AA-speaking groups in the region, suggesting an impact of cultural diffusion. Overall, we provide the first detailed insights into the genetic profiles of Thai/Lao ethnolinguistic groups, which should be helpful for reconstructing human genetic history in MSEA and selecting populations for participation in ongoing whole genome sequence and biomedical studies.

Advancing drug discovery using the power of the human genome.

Human genetics plays an increasingly important role in drug development and population health. Here we review the history of human genetics in the context of accelerating the discovery of therapies, present examples of how human genetics evidence supports successful drug targets, and discuss how polygenic risk scores could be beneficial in various clinical settings. We highlight the value of direct‐to‐consumer platforms in the era of fast‐paced big data biotechnology, and how diverse genetic and health data can benefit society. © 2021 23andMe, Inc. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Human molecular evolutionary rate, time dependency and transient polymorphism effects viewed through ancient and modern mitochondrial DNA genomes

Human evolutionary genetics gives a chronological framework to interpret the human history. It is based on the molecular clock hypothesis that suppose a straightforward relationship between the mutation rate and the substitution rate with independence of other factors as demography dynamics. Analyzing ancient and modern human complete mitochondrial genomes we show here that, along the time, the substitution rate can be significantly slower or faster than the average germline mutation rate confirming a time dependence effect mainly attributable to changes in the effective population size of the human populations, with an exponential growth in recent times. We also detect that transient polymorphisms play a slowdown role in the evolutionary rate deduced from haplogroup intraspecific trees. Finally, we propose the use of the most divergent lineages within haplogroups as a practical approach to correct these molecular clock mismatches.

Insights into human genetic variation and population history from 929 diverse genomes

Genome sequences from diverse human groups are needed to understand the structure of genetic variation in our species and the history of, and relationships between, different populations. We present 929 high-coverage genome sequences from 54 diverse human populations, 26 of which are physically phased using linked-read sequencing. Analyses of these genomes reveal an excess of previously undocumented common genetic variation private to southern Africa, central Africa, Oceania, and the Americas, but an absence of such variants fixed between major geographical regions. We also find deep and gradual population separations within Africa, contrasting population size histories between hunter-gatherer and agriculturalist groups in the past 10,000 years, and a contrast between single Neanderthal but multiple Denisovan source populations contributing to present-day human populations.

Genetic structure and forensic characterisation of 36 Y-chromosomal STR loci in Hmong-Mien-speaking Miao population

Background Y-chromosomal short tandem repeats (Y-STRs) are widely used in paternity identification, pedigree investigation, and human population genetic history. Aim To investigate the Y-STR polymorphisms in a typical Miao population, and explore the genetic differentiation between the Miao population and reference groups. Subjects and methods We detected 36 Y-STRs genotyping in 455 unrelated Miao individuals from Guizhou province, and analysed genetic differentiation between the Miao population and 76 reference groups. Results A total of 369 alleles were obtained, and the allele frequencies ranged from 0.0022 to 0.9802. In addition, the haplotype diversity, random match probability, and discrimination capacity values were 0.99997, 0.0022, and 0.9934, respectively. Moreover, the genetic relationships between Guizhou Miao and 76 ethnic populations showed that the population stratification was almost consistent with geographic distribution and language-family. Conclusions The 36 Y-STR loci in this study have good polymorphism distributions in the Guizhou Miao population, and therefore would be a useful tool in forensic identification and male parentage testing and even pedigree investigation.

P0050PRE-IMPLANTATION GENETIC TESTING FOR MONOGENIC KIDNEY DISEASE: TWENTY-FIVE YEAR EXPERIENCE IN THE NETHERLANDS

Abstract Background and Aims Due to the fast-paced developments in human genetics, a genetic cause can now be identified for an increasing number of pediatric and adult-onset kidney diseases. A monogenic kidney disease (MKD) can impact prognostication and therapy decisions. It also provides patients with options regarding family planning such as preimplantation genetic testing (PGT), a reproductive technology that helps prospective parents prevent passing on a disease-causing mutation to their offspring. There are limited reports on PGT for MKD and most are focused on severe pediatric-onset diseases. The Dutch system of insurance reimbursement and nationwide regulation is unique, and it has allowed the Netherlands to be one of a handful of countries where couples have the option to choose PGT for MKD, including adult-onset forms of kidney disease. Here we provide the 25-year Dutch experience with PGT for MKD. Method We performed a retrospective cohort study of all couples counselled on PGT for MKD in the Maastricht University Medical Center+, the expert centre where all Dutch single cell genetic testing on embryos is performed, from January 1995 until June 2019. Results 99 couples were counseled for PGT, of which currently 15% is waiting for the genetic test to be validated. In the early years of PGT for MKD, referrals were incidental and only for couples at risk for offspring with paediatric-onset disease. From 2009 onwards, the number of referrals has steadily increased as has the number of couples referred for adult-onset MKD. Overall, the most frequent indications for referral for PGT were ADPKD (37%), X-linked Alport syndrome (25%) and ARPKD (9%). After counselling, 36% of n=99 couples started PGT treatment. In total n=80 cycles with oocyte retrieval were performed (median 2 cycles [range 1-4]). These cycles led to a median of n=10 embryos (range 2-31) suitable for biopsy and a median of n=3 embryos (range 1-14) being genetically unaffected. Seventy-five percent (n=) of couples achieved at least one live birth. Of n=99, 48% did not proceed with PGT, for various personal and technical reasons. Major reasons for opting out of PGT were that prospective parents did not want to wait for the lengthy PGT procedure (9%) or had a wish for natural conception with prenatal genetic testing (11%). Live birth rate was 40% (n=19) in the non-PGT group, with notably a similar duration to a live birth as the PGT group (2 years, range 0-5 years). Conclusion We provide the largest overview to date of the indications, uptake and results of PGT for MKD. Referrals for PGT, including adult-onset disease, have increased steadily over the past decade. PGT has favorable outcomes, with 75% of couples having at least one live birth, though this is likely due to our small sample size. Genetic and reproductive counseling, including information on PGT, should be provided to all patients and prospective parents from families with MKD to enable informed decision making.

Interbreeding between archaic human groups and anatomically modern humans commonly occurring in prehistory

A hominin bone fragment from Denisova Cave (Russia) was identified among very few archaic human specimens (i.e., Neanderthals and Denisovans) as being the first-generation offspring of a Neanderthal mother and a Denisovan father. The ancient genomic study of this individual, together with previous evidence of interbreeding, suggests that admixture between archaic and modern humans was common. Here, we review the evidence for hominin interbreeding and the impact of introgressed archaic human DNA on modern humans. As the recovery of human remains in the Pleistocene is extremely rare, a collagen fingerprinting method, often referred to as Zooarchaeology by Mass Spectrometry (ZooMS), was applied to identify over 2000 fragmented bones from Denisova Cave with one being of hominin origin. This individual, named Denisova 11, had her genome sequenced to an average coverage of 2.6-fold. Her mitochondrial DNA was found to be of the Neanderthal type and direct radiocarbon dating showed her to be more than 50000 years old. Approximately equal proportions of Neanderthal-like and Denisovan-like alleles were found in the Denisova 11 individual. This can be explained by her belonging to a population with mixed Neanderthal and Denisovan ancestry, or by her parents being from each one of these two groups. After excluding any accidental mixing of DNA in the laboratory or systematic errors in data processing, analysis of the individual’s alleles carried by two randomly drawn DNA fragments indicated that she had a Neanderthal mother and a Denisovan father. Interbreeding between archaic and modern humans outside Africa was confirmed by a series of studies since the draft sequence of the Neanderthal genome was published in 2010; non-Africans today are the products of this mixture. The proportion of Neanderthal ancestry is significantly higher in present-day East Asians (2.3%−2.6%) than in Western Eurasians (1.8%−2.4%). This has been explained by two independent Neanderthal gene flow events, a later out-of-Africa migration that diluted the proportion of Neanderthal ancestry in Western Eurasian ancestors, or by purifying selection in different population groups. A recent study found that African populations have more Neanderthal ancestry than previously thought, which can be explained by back-migration of Europeans carrying Neanderthal ancestry into Africa. Another widely-known archaic human group, the Denisovans, was identified by the ancient DNA extracted from a finger bone found in Denisova Cave. Along with the high proportion (~5%) of ancestry contributed to present-day Melanesians in Oceania, Denisovans also contributed ~0.2% to the ancestry of mainland Asian and Native American populations. Genes flow into Denisovans from Neanderthals and an unknown hominin (“super-archaic”) were also suggested by ancient DNA studies. Archaeological, ancient genomic, and ancient protein studies suggest Denisovans may have had a wide ecological and geographic distribution. Overall, frequent admixture among different human groups resulted in ~2% Neanderthal ancestry in all non-African humans and up to 5% Denisovan ancestry in some present-day Oceanians. The introgressed archaic human DNA in present-day humans have been affected by natural selection, and inferences about the functional, evolutionary, and phenotypic significance reveal both positive and negative effects. Functional regions of modern human genomes have fewer archaic alleles than expected under a neutral demographic model, which suggests a reduced fitness of some archaic alleles in modern humans. Many Neanderthal variants associated with phenotypes and susceptibility to diseases have been identified in present-day non-Africans, such as type 2 diabetes, lupus, biliary cirrhosis, etc. However, many of the introgressed tracts are also functionally important and possibly helped modern humans adapt to different environments, such as high altitude and latitude areas. For example, the EPAS1 and WARS2/TBX15 , are associated with a high-altitude and high-latitude adaptation in Tibetans and Greenlandic Inuits, respectively. These findings illustrate that admixture with archaic humans has provided genetic variation that helped humans adapt to new environments and has continued to shape our biology. We expect that in the future there will be more evidence of interbreeding between humans in different areas and time periods, adding more details to human genetic history.

Insights into human genetic variation and population history from 929 diverse genomes.

Genome sequences from diverse human groups are needed to understand the structure of genetic variation in our species and the history of, and relationships between, different populations. We present 929 high-coverage genome sequences from 54 diverse human populations, 26 of which are physically phased using linked-read sequencing. Analyses of these genomes reveal an excess of previously undocumented common genetic variation private to southern Africa, central Africa, Oceania, and the Americas, but an absence of such variants fixed between major geographical regions. We also find deep and gradual population separations within Africa, contrasting population size histories between hunter-gatherer and agriculturalist groups in the past 10,000 years, and a contrast between single Neanderthal but multiple Denisovan source populations contributing to present-day human populations.