Publications by authors named "Chris Tyler-Smith"

215 Publications

A common 1.6 mb Y-chromosomal inversion predisposes to subsequent deletions and severe spermatogenic failure in humans.

Elife 2021 03 30;10. Epub 2021 Mar 30.

Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.

Male infertility is a prevalent condition, affecting 5-10% of men. So far, few genetic factors have been described as contributors to spermatogenic failure. Here, we report the first re-sequencing study of the Y-chromosomal () region, combined with gene dosage analysis of the multicopy , and genes and Y-haplogroup determination. In analysing 2324 Estonian men, we uncovered a novel structural variant as a high-penetrance risk factor for male infertility. The Y lineage R1a1-M458, reported at >20% frequency in several European populations, carries a fixed ~1.6 Mb inversion, destabilizing the region and predisposing to large recurrent microdeletions. Such complex rearrangements were significantly enriched among severe oligozoospermia cases. The carrier vs non-carrier risk for spermatogenic failure was increased 8.6-fold (p=6.0×10). This finding contributes to improved molecular diagnostics and clinical management of infertility. Carrier identification at young age will facilitate timely counselling and reproductive decision-making.
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http://dx.doi.org/10.7554/eLife.65420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009663PMC
March 2021

The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects.

Am J Hum Genet 2021 04 18;108(4):608-619. Epub 2021 Mar 18.

Department of Human Genetics and Donders Center for Neuroscience, Radboud University Medical Centre, Nijmegen 6525 GA, the Netherlands; Department of Clinical Genetics, GROW-School for Oncology and Developmental Biology and MHENS School for Mental Health and Neuroscience, Maastricht University Medical Center, PO Box 5800, Maastricht 6202AZ, the Netherlands. Electronic address:

The number and distribution of recessive alleles in the population for various diseases are not known at genome-wide-scale. Based on 6,447 exome sequences of healthy, genetically unrelated Europeans of two distinct ancestries, we estimate that every individual is a carrier of at least 2 pathogenic variants in currently known autosomal-recessive (AR) genes and that 0.8%-1% of European couples are at risk of having a child affected with a severe AR genetic disorder. This risk is 16.5-fold higher for first cousins but is significantly more increased for skeletal disorders and intellectual disabilities due to their distinct genetic architecture.
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http://dx.doi.org/10.1016/j.ajhg.2021.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059335PMC
April 2021

Subdividing Y-chromosome haplogroup R1a1 reveals Norse Viking dispersal lineages in Britain.

Eur J Hum Genet 2021 Mar 2;29(3):512-523. Epub 2020 Nov 2.

Department of Genetics & Genome Biology, University of Leicester, Leicester, UK.

The influence of Viking-Age migrants to the British Isles is obvious in archaeological and place-names evidence, but their demographic impact has been unclear. Autosomal genetic analyses support Norse Viking contributions to parts of Britain, but show no signal corresponding to the Danelaw, the region under Scandinavian administrative control from the ninth to eleventh centuries. Y-chromosome haplogroup R1a1 has been considered as a possible marker for Viking migrations because of its high frequency in peninsular Scandinavia (Norway and Sweden). Here we select ten Y-SNPs to discriminate informatively among hg R1a1 sub-haplogroups in Europe, analyse these in 619 hg R1a1 Y chromosomes including 163 from the British Isles, and also type 23 short-tandem repeats (Y-STRs) to assess internal diversity. We find three specifically Western-European sub-haplogroups, two of which predominate in Norway and Sweden, and are also found in Britain; star-like features in the STR networks of these lineages indicate histories of expansion. We ask whether geographical distributions of hg R1a1 overall, and of the two sub-lineages in particular, correlate with regions of Scandinavian influence within Britain. Neither shows any frequency difference between regions that have higher (≥10%) or lower autosomal contributions from Norway and Sweden, but both are significantly overrepresented in the region corresponding to the Danelaw. These differences between autosomal and Y-chromosomal histories suggest either male-specific contribution, or the influence of patrilocality. Comparison of modern DNA with recently available ancient DNA data supports the interpretation that two sub-lineages of hg R1a1 spread with the Vikings from peninsular Scandinavia.
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http://dx.doi.org/10.1038/s41431-020-00747-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940619PMC
March 2021

Positive selection in admixed populations from Ethiopia.

BMC Genet 2020 10 22;21(Suppl 1):108. Epub 2020 Oct 22.

Institut de Biologia Evolutiva (UPF-CSIC), Universitat Pompeu Fabra, Dr. Aiguader, 88 08003, Barcelona, Catalonia, Spain.

Background: In the process of adaptation of humans to their environment, positive or adaptive selection has played a main role. Positive selection has, however, been under-studied in African populations, despite their diversity and importance for understanding human history.

Results: Here, we have used 119 available whole-genome sequences from five Ethiopian populations (Amhara, Oromo, Somali, Wolayta and Gumuz) to investigate the modes and targets of positive selection in this part of the world. The site frequency spectrum-based test SFselect was applied to idfentify a wide range of events of selection (old and recent), and the haplotype-based statistic integrated haplotype score to detect more recent events, in each case with evaluation of the significance of candidate signals by extensive simulations. Additional insights were provided by considering admixture proportions and functional categories of genes. We identified both individual loci that are likely targets of classic sweeps and groups of genes that may have experienced polygenic adaptation. We found population-specific as well as shared signals of selection, with folate metabolism and the related ultraviolet response and skin pigmentation standing out as a shared pathway, perhaps as a response to the high levels of ultraviolet irradiation, and in addition strong signals in genes such as IFNA, MRC1, immunoglobulins and T-cell receptors which contribute to defend against pathogens.

Conclusions: Signals of positive selection were detected in Ethiopian populations revealing novel adaptations in East Africa, and abundant targets for functional follow-up.
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http://dx.doi.org/10.1186/s12863-020-00908-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580818PMC
October 2020

A Southeast Asian origin for present-day non-African human Y chromosomes.

Hum Genet 2021 Feb 14;140(2):299-307. Epub 2020 Jul 14.

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.

The genomes of present-day humans outside Africa originated almost entirely from a single out-migration ~ 50,000-70,000 years ago, followed by mixture with Neanderthals contributing ~ 2% to all non-Africans. However, the details of this initial migration remain poorly understood because no ancient DNA analyses are available from this key time period, and interpretation of present-day autosomal data is complicated due to subsequent population movements/reshaping. One locus, however, does retain male-specific information from this early period: the Y chromosome, where a detailed calibrated phylogeny has been constructed. Three present-day Y lineages were carried by the initial migration: the rare haplogroup D, the moderately rare C, and the very common FT lineage which now dominates most non-African populations. Here, we show that phylogenetic analyses of haplogroup C, D and FT sequences, including very rare deep-rooting lineages, together with phylogeographic analyses of ancient and present-day non-African Y chromosomes, all point to East/Southeast Asia as the origin 50,000-55,000 years ago of all known surviving non-African male lineages (apart from recent migrants). This observation contrasts with the expectation of a West Eurasian origin predicted by a simple model of expansion from a source near Africa, and can be interpreted as resulting from extensive genetic drift in the initial population or replacement of early western Y lineages from the east, thus informing and constraining models of the initial expansion.
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http://dx.doi.org/10.1007/s00439-020-02204-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864842PMC
February 2021

Population Structure, Stratification, and Introgression of Human Structural Variation.

Cell 2020 07 11;182(1):189-199.e15. Epub 2020 Jun 11.

Wellcome Sanger Institute, Hinxton CB10 1SA, UK. Electronic address:

Structural variants contribute substantially to genetic diversity and are important evolutionarily and medically, but they are still understudied. Here we present a comprehensive analysis of structural variation in the Human Genome Diversity panel, a high-coverage dataset of 911 samples from 54 diverse worldwide populations. We identify, in total, 126,018 variants, 78% of which were not identified in previous global sequencing projects. Some reach high frequency and are private to continental groups or even individual populations, including regionally restricted runaway duplications and putatively introgressed variants from archaic hominins. By de novo assembly of 25 genomes using linked-read sequencing, we discover 1,643 breakpoint-resolved unique insertions, in aggregate accounting for 1.9 Mb of sequence absent from the GRCh38 reference. Our results illustrate the limitation of a single human reference and the need for high-quality genomes from diverse populations to fully discover and understand human genetic variation.
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http://dx.doi.org/10.1016/j.cell.2020.05.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369638PMC
July 2020

A Genetic History of the Near East from an aDNA Time Course Sampling Eight Points in the Past 4,000 Years.

Am J Hum Genet 2020 07 28;107(1):149-157. Epub 2020 May 28.

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK. Electronic address:

The Iron and Classical Ages in the Near East were marked by population expansions carrying cultural transformations that shaped human history, but the genetic impact of these events on the people who lived through them is little-known. Here, we sequenced the whole genomes of 19 individuals who each lived during one of four time periods between 800 BCE and 200 CE in Beirut on the Eastern Mediterranean coast at the center of the ancient world's great civilizations. We combined these data with published data to traverse eight archaeological periods and observed any genetic changes as they arose. During the Iron Age (∼1000 BCE), people with Anatolian and South-East European ancestry admixed with people in the Near East. The region was then conquered by the Persians (539 BCE), who facilitated movement exemplified in Beirut by an ancient family with Egyptian-Lebanese admixed members. But the genetic impact at a population level does not appear until the time of Alexander the Great (beginning 330 BCE), when a fusion of Asian and Near Easterner ancestry can be seen, paralleling the cultural fusion that appears in the archaeological records from this period. The Romans then conquered the region (31 BCE) but had little genetic impact over their 600 years of rule. Finally, during the Ottoman rule (beginning 1516 CE), Caucasus-related ancestry penetrated the Near East. Thus, in the past 4,000 years, three limited admixture events detectably impacted the population, complementing the historical records of this culturally complex region dominated by the elite with genetic insights from the general population.
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http://dx.doi.org/10.1016/j.ajhg.2020.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332655PMC
July 2020

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

Science 2020 03;367(6484)

Wellcome Sanger Institute, Hinxton CB10 1SA, UK.

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.
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http://dx.doi.org/10.1126/science.aay5012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115999PMC
March 2020

Uganda Genome Resource Enables Insights into Population History and Genomic Discovery in Africa.

Cell 2019 10;179(4):984-1002.e36

Wellcome Sanger Institute, Hinxton, Cambridge, UK.

Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans was best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, hematological, lipid, and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region.
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http://dx.doi.org/10.1016/j.cell.2019.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202134PMC
October 2019

Birth, expansion, and death of VCY-containing palindromes on the human Y chromosome.

Genome Biol 2019 10 14;20(1):207. Epub 2019 Oct 14.

The Wellcome Sanger Institute, Hinxton, Cambridgeshire, CB10 1SA, UK.

Background: Large palindromes (inverted repeats) make up substantial proportions of mammalian sex chromosomes, often contain genes, and have high rates of structural variation arising via ectopic recombination. As a result, they underlie many genomic disorders. Maintenance of the palindromic structure by gene conversion between the arms has been documented, but over longer time periods, palindromes are remarkably labile. Mechanisms of origin and loss of palindromes have, however, received little attention.

Results: Here, we use fiber-FISH, 10x Genomics Linked-Read sequencing, and breakpoint PCR sequencing to characterize the structural variation of the P8 palindrome on the human Y chromosome, which contains two copies of the VCY (Variable Charge Y) gene. We find a deletion of almost an entire arm of the palindrome, leading to death of the palindrome, a size increase by recruitment of adjacent sequence, and other complex changes including the formation of an entire new palindrome nearby. Together, these changes are found in ~ 1% of men, and we can assign likely molecular mechanisms to these mutational events. As a result, healthy men can have 1-4 copies of VCY.

Conclusions: Gross changes, especially duplications, in palindrome structure can be relatively frequent and facilitate the evolution of sex chromosomes in humans, and potentially also in other mammalian species.
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http://dx.doi.org/10.1186/s13059-019-1816-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790999PMC
October 2019

A Rare Deep-Rooting D0 African Y-Chromosomal Haplogroup and Its Implications for the Expansion of Modern Humans Out of Africa.

Genetics 2019 08 13;212(4):1421-1428. Epub 2019 Jun 13.

The Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK

Present-day humans outside Africa descend mainly from a single expansion out ∼50,000-70,000 years ago, but many details of this expansion remain unclear, including the history of the male-specific Y chromosome at this time. Here, we reinvestigate a rare deep-rooting African Y-chromosomal lineage by sequencing the whole genomes of three Nigerian men described in 2003 as carrying haplogroup DE* Y chromosomes, and analyzing them in the context of a calibrated worldwide Y-chromosomal phylogeny. We confirm that these three chromosomes do represent a deep-rooting DE lineage, branching close to the DE bifurcation, but place them on the D branch as an outgroup to all other known D chromosomes, and designate the new lineage D0. We consider three models for the expansion of Y lineages out of Africa ∼50,000-100,000 years ago, incorporating migration back to Africa where necessary to explain present-day Y-lineage distributions. Considering both the Y-chromosomal phylogenetic structure incorporating the D0 lineage, and published evidence for modern humans outside Africa, the most favored model involves an origin of the DE lineage within Africa with D0 and E remaining there, and migration out of the three lineages (C, D, and FT) that now form the vast majority of non-African Y chromosomes. The exit took place 50,300-81,000 years ago (latest date for FT lineage expansion outside Africa - earliest date for the D/D0 lineage split inside Africa), and most likely 50,300-59,400 years ago (considering Neanderthal admixture). This work resolves a long-running debate about Y-chromosomal out-of-Africa/back-to-Africa migrations, and provides insights into the out-of-Africa expansion more generally.
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http://dx.doi.org/10.1534/genetics.119.302368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707464PMC
August 2019

How well do we understand the basis of classic selective sweeps in humans?

FEBS Lett 2019 07 11;593(13):1431-1448. Epub 2019 Jun 11.

The Wellcome Sanger Institute, Hinxton, UK.

Classic selective sweeps occur when positive selection increases a variant's frequency from low to high in a population, and underlie some long-studied human characteristics such as variation in skin, hair or eye colour. In such well-studied 'gold standard' examples, a known variant has been associated with a plausible phenotype and underlying selective force. Signatures of classic sweeps have more recently been detected in population-genetic data independently of any prior information about the corresponding phenotype or selective force, and usually without suggesting any insights into these. Motivated by the need to understand such candidates, we first review the gold standards and show that our understanding of them is often incomplete or unconvincing; only two of the examples we consider are compellingly explained. We assess approaches for large-scale association of classic sweep candidate variants to phenotypes and selective forces, test these on the gold standards, and discuss the standards of evidence needed to adequately understand a selective sweep.
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http://dx.doi.org/10.1002/1873-3468.13447DOI Listing
July 2019

Evolutionary and functional analysis of RBMY1 gene copy number variation on the human Y chromosome.

Hum Mol Genet 2019 08;28(16):2785-2798

Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.

Human RBMY1 genes are located in four variable-sized clusters on the Y chromosome, expressed in male germ cells and possibly associated with sperm motility. We have re-investigated the mutational background and evolutionary history of the RBMY1 copy number distribution in worldwide samples and its relevance to sperm parameters in an Estonian cohort of idiopathic male factor infertility subjects. We estimated approximate RBMY1 copy numbers in 1218 1000 Genomes Project phase 3 males from sequencing read-depth, then chose 14 for valid ation by multicolour fibre-FISH. These fibre-FISH samples provided accurate calibration standards for the entire panel and led to detailed insights into population variation and mutational mechanisms. RBMY1 copy number worldwide ranged from 3 to 13 with a mode of 8. The two larger proximal clusters were the most variable, and additional duplications, deletions and inversions were detected. Placing the copy number estimates onto the published Y-SNP-based phylogeny of the same samples suggested a minimum of 562 mutational changes, translating to a mutation rate of 2.20 × 10-3 (95% CI 1.94 × 10-3 to 2.48 × 10-3) per father-to-son Y-transmission, higher than many short tandem repeat (Y-STRs), and showed no evidence for selection for increased or decreased copy number, but possible copy number stabilizing selection. An analysis of RBMY1 copy numbers among 376 infertility subjects failed to replicate a previously reported association with sperm motility and showed no significant effect on sperm count and concentration, serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone levels or testicular and semen volume. These results provide the first in-depth insights into the structural rearrangements underlying RBMY1 copy number variation across diverse human lineages.
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http://dx.doi.org/10.1093/hmg/ddz101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687947PMC
August 2019

A Transient Pulse of Genetic Admixture from the Crusaders in the Near East Identified from Ancient Genome Sequences.

Am J Hum Genet 2019 05 18;104(5):977-984. Epub 2019 Apr 18.

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK. Electronic address:

During the medieval period, hundreds of thousands of Europeans migrated to the Near East to take part in the Crusades, and many of them settled in the newly established Christian states along the Eastern Mediterranean coast. Here, we present a genetic snapshot of these events and their aftermath by sequencing the whole genomes of 13 individuals who lived in what is today known as Lebanon between the 3 and 13 centuries CE. These include nine individuals from the "Crusaders' pit" in Sidon, a mass burial in South Lebanon identified from the archaeology as the grave of Crusaders killed during a battle in the 13 century CE. We show that all of the Crusaders' pit individuals were males; some were Western Europeans from diverse origins, some were locals (genetically indistinguishable from present-day Lebanese), and two individuals were a mixture of European and Near Eastern ancestries, providing direct evidence that the Crusaders admixed with the local population. However, these mixtures appear to have had limited genetic consequences since signals of admixture with Europeans are not significant in any Lebanese group today-in particular, Lebanese Christians are today genetically similar to local people who lived during the Roman period which preceded the Crusades by more than four centuries.
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http://dx.doi.org/10.1016/j.ajhg.2019.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506814PMC
May 2019

Positive selection in Europeans and East-Asians at the ABCA12 gene.

Sci Rep 2019 03 19;9(1):4843. Epub 2019 Mar 19.

Institute of Genetics and Biophysics, National Research Council, Naples, Italy.

Natural selection acts on genetic variants by increasing the frequency of alleles responsible for a cellular function that is favorable in a certain environment. In a previous genome-wide scan for positive selection in contemporary humans, we identified a signal of positive selection in European and Asians at the genetic variant rs10180970. The variant is located in the second intron of the ABCA12 gene, which is implicated in the lipid barrier formation and down-regulated by UVB radiation. We studied the signal of selection in the genomic region surrounding rs10180970 in a larger dataset that includes DNA sequences from ancient samples. We also investigated the functional consequences of gene expression of the alleles of rs10180970 and another genetic variant in its proximity in healthy volunteers exposed to similar UV radiation. We confirmed the selection signal and refine its location that extends over 35 kb and includes the first intron, the first two exons and the transcription starting site of ABCA12. We found no obvious effect of rs10180970 alleles on ABCA12 gene expression. We reconstructed the trajectory of the T allele over the last 80,000 years to discover that it was specific to H. sapiens and present in non-Africans 45,000 years ago.
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http://dx.doi.org/10.1038/s41598-019-40360-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424970PMC
March 2019

Y Chromosome Sequences Reveal a Short Beringian Standstill, Rapid Expansion, and early Population structure of Native American Founders.

Curr Biol 2019 01 20;29(1):149-157.e3. Epub 2018 Dec 20.

The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK. Electronic address:

The Americas were the last inhabitable continents to be occupied by humans, with a growing multidisciplinary consensus for entry 15-25 thousand years ago (kya) from northeast Asia via the former Beringia land bridge [1-4]. Autosomal DNA analyses have dated the separation of Native American ancestors from the Asian gene pool to 23 kya or later [5, 6] and mtDNA analyses to ∼25 kya [7], followed by isolation ("Beringian Standstill" [8, 9]) for 2.4-9 ky and then a rapid expansion throughout the Americas. Here, we present a calibrated sequence-based analysis of 222 Native American and relevant Eurasian Y chromosomes (24 new) from haplogroups Q and C [10], with four major conclusions. First, we identify three to four independent lineages as autochthonous and likely founders: the major Q-M3 and rarer Q-CTS1780 present throughout the Americas, the very rare C3-MPB373 in South America, and possibly the C3-P39/Z30536 in North America. Second, from the divergence times and Eurasian/American distribution of lineages, we estimate a Beringian Standstill duration of 2.7 ky or 4.6 ky, according to alternative models, and entry south of the ice sheet after 19.5 kya. Third, we describe the star-like expansion of Q-M848 (within Q-M3) starting at 15 kya [11] in the Americas, followed by establishment of substantial spatial structure in South America by 12 kya. Fourth, the deep branches of the Q-CTS1780 lineage present at low frequencies throughout the Americas today [12] may reflect a separate out-of-Beringia dispersal after the melting of the glaciers at the end of the Pleistocene.
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http://dx.doi.org/10.1016/j.cub.2018.11.029DOI Listing
January 2019

Ancient human parallel lineages within North America contributed to a coastal expansion.

Science 2018 06;360(6392):1024-1027

Huron-Wendat Nation, Canada.

Little is known regarding the first people to enter the Americas and their genetic legacy. Genomic analysis of the oldest human remains from the Americas showed a direct relationship between a Clovis-related ancestral population and all modern Central and South Americans as well as a deep split separating them from North Americans in Canada. We present 91 ancient human genomes from California and Southwestern Ontario and demonstrate the existence of two distinct ancestries in North America, which possibly split south of the ice sheets. A contribution from both of these ancestral populations is found in all modern Central and South Americans. The proportions of these two ancestries in ancient and modern populations are consistent with a coastal dispersal and multiple admixture events.
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http://dx.doi.org/10.1126/science.aar6851DOI Listing
June 2018

Demographic History and Genetic Adaptation in the Himalayan Region Inferred from Genome-Wide SNP Genotypes of 49 Populations.

Mol Biol Evol 2018 08;35(8):1916-1933

The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom.

We genotyped 738 individuals belonging to 49 populations from Nepal, Bhutan, North India, or Tibet at over 500,000 SNPs, and analyzed the genotypes in the context of available worldwide population data in order to investigate the demographic history of the region and the genetic adaptations to the harsh environment. The Himalayan populations resembled other South and East Asians, but in addition displayed their own specific ancestral component and showed strong population structure and genetic drift. We also found evidence for multiple admixture events involving Himalayan populations and South/East Asians between 200 and 2,000 years ago. In comparisons with available ancient genomes, the Himalayans, like other East and South Asian populations, showed similar genetic affinity to Eurasian hunter-gatherers (a 24,000-year-old Upper Palaeolithic Siberian), and the related Bronze Age Yamnaya. The high-altitude Himalayan populations all shared a specific ancestral component, suggesting that genetic adaptation to life at high altitude originated only once in this region and subsequently spread. Combining four approaches to identifying specific positively selected loci, we confirmed that the strongest signals of high-altitude adaptation were located near the Endothelial PAS domain-containing protein 1 and Egl-9 Family Hypoxia Inducible Factor 1 loci, and discovered eight additional robust signals of high-altitude adaptation, five of which have strong biological functional links to such adaptation. In conclusion, the demographic history of Himalayan populations is complex, with strong local differentiation, reflecting both genetic and cultural factors; these populations also display evidence of multiple genetic adaptations to high-altitude environments.
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http://dx.doi.org/10.1093/molbev/msy094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063301PMC
August 2018

Human Genetics: Busy Subway Networks in Remote Oceania?

Curr Biol 2018 05;28(9):R549-R551

The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK.

Ancient human DNA from the Oceanian islands of Vanuatu reveals a surprisingly complex history of human settlement, featuring almost complete replacement shortly after initial colonisation, followed by mixing and a puzzling disconnect between genetic ancestry and language.
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http://dx.doi.org/10.1016/j.cub.2018.03.033DOI Listing
May 2018

FineMAV: prioritizing candidate genetic variants driving local adaptations in human populations.

Genome Biol 2018 01 17;19(1). Epub 2018 Jan 17.

Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK.

We present a new method, Fine-Mapping of Adaptive Variation (FineMAV), which combines population differentiation, derived allele frequency, and molecular functionality to prioritize positively selected candidate variants for functional follow-up. We calibrate and test FineMAV using eight experimentally validated "gold standard" positively selected variants and simulations. FineMAV has good sensitivity and a low false discovery rate. Applying FineMAV to the 1000 Genomes Project Phase 3 SNP dataset, we report many novel selected variants, including ones in TGM3 and PRSS53 associated with hair phenotypes that we validate using available independent data. FineMAV is widely applicable to sequence data from both human and other species.
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http://dx.doi.org/10.1186/s13059-017-1380-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771147PMC
January 2018

Copy number variation arising from gene conversion on the human Y chromosome.

Hum Genet 2018 Jan 5;137(1):73-83. Epub 2017 Dec 5.

Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.

We describe the variation in copy number of a ~ 10 kb region overlapping the long intergenic noncoding RNA (lincRNA) gene, TTTY22, within the IR3 inverted repeat on the short arm of the human Y chromosome, leading to individuals with 0-3 copies of this region in the general population. Variation of this CNV is common, with 266 individuals having 0 copies, 943 (including the reference sequence) having 1, 23 having 2 copies, and two having 3 copies, and was validated by breakpoint PCR, fibre-FISH, and 10× Genomics Chromium linked-read sequencing in subsets of 1234 individuals from the 1000 Genomes Project. Mapping the changes in copy number to the phylogeny of these Y chromosomes previously established by the Project identified at least 20 mutational events, and investigation of flanking paralogous sequence variants showed that the mutations involved flanking sequences in 18 of these, and could extend over > 30 kb of DNA. While either gene conversion or double crossover between misaligned sister chromatids could formally explain the 0-2 copy events, gene conversion is the more likely mechanism, and these events include the longest non-allelic gene conversion reported thus far. Chromosomes with three copies of this CNV have arisen just once in our data set via another mechanism: duplication of 420 kb that places the third copy 230 kb proximal to the existing proximal copy. Our results establish gene conversion as a previously under-appreciated mechanism of generating copy number changes in humans and reveal the exceptionally large size of the conversion events that can occur.
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http://dx.doi.org/10.1007/s00439-017-1857-9DOI Listing
January 2018

The Genetic Legacy of the Indian Ocean Slave Trade: Recent Admixture and Post-admixture Selection in the Makranis of Pakistan.

Am J Hum Genet 2017 Dec 9;101(6):977-984. Epub 2017 Nov 9.

Unit of Human Evolutionary Genetics, Department of Genomes & Genetics, Institut Pasteur, Paris 75015, France; Centre National de la Recherche Scientifique URA3012, Paris 75015, France; Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, Paris 75015, France. Electronic address:

From the eighth century onward, the Indian Ocean was the scene of extensive trade of sub-Saharan African slaves via sea routes controlled by Muslim Arab and Swahili traders. Several populations in present-day Pakistan and India are thought to be the descendants of such slaves, yet their history of admixture and natural selection remains largely undefined. Here, we studied the genome-wide diversity of the African-descent Makranis, who reside on the Arabian Sea coast of Pakistan, as well that of four neighboring Pakistani populations, to investigate the genetic legacy, population dynamics, and tempo of the Indian Ocean slave trade. We show that the Makranis are the result of an admixture event between local Baluch tribes and Bantu-speaking populations from eastern or southeastern Africa; we dated this event to ∼300 years ago during the Omani Empire domination. Levels of parental relatedness, measured through runs of homozygosity, were found to be similar across Pakistani populations, suggesting that the Makranis rapidly adopted the traditional practice of endogamous marriages. Finally, we searched for signatures of post-admixture selection at traits evolving under positive selection, including skin color, lactase persistence, and resistance to malaria. We demonstrate that the African-specific Duffy-null blood group-believed to confer resistance against Plasmodium vivax infection-was recently introduced to Pakistan through the slave trade and evolved adaptively in this P. vivax malaria-endemic region. Our study reconstructs the genetic and adaptive history of a neglected episode of the African Diaspora and illustrates the impact of recent admixture on the diffusion of adaptive traits across human populations.
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http://dx.doi.org/10.1016/j.ajhg.2017.09.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812914PMC
December 2017

Paleolithic networking.

Science 2017 11;358(6363):586-587

The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.

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http://dx.doi.org/10.1126/science.aaq0771DOI Listing
November 2017

A Neolithic expansion, but strong genetic structure, in the independent history of New Guinea.

Science 2017 09;357(6356):1160-1163

Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

New Guinea shows human occupation since ~50 thousand years ago (ka), independent adoption of plant cultivation ~10 ka, and great cultural and linguistic diversity today. We performed genome-wide single-nucleotide polymorphism genotyping on 381 individuals from 85 language groups in Papua New Guinea and find a sharp divide originating 10 to 20 ka between lowland and highland groups and a lack of non-New Guinean admixture in the latter. All highlanders share ancestry within the last 10 thousand years, with major population growth in the same period, suggesting population structure was reshaped following the Neolithic lifestyle transition. However, genetic differentiation between groups in Papua New Guinea is much stronger than in comparable regions in Eurasia, demonstrating that such a transition does not necessarily limit the genetic and linguistic diversity of human societies.
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http://dx.doi.org/10.1126/science.aan3842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802383PMC
September 2017

Estimating the human mutation rate from autozygous segments reveals population differences in human mutational processes.

Nat Commun 2017 08 21;8(1):303. Epub 2017 Aug 21.

Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.

Heterozygous mutations within homozygous sequences descended from a recent common ancestor offer a way to ascertain de novo mutations across multiple generations. Using exome sequences from 3222 British-Pakistani individuals with high parental relatedness, we estimate a mutation rate of 1.45 ± 0.05 × 10 per base pair per generation in autosomal coding sequence, with a corresponding non-crossover gene conversion rate of 8.75 ± 0.05 × 10 per base pair per generation. This is at the lower end of exome mutation rates previously estimated in parent-offspring trios, suggesting that post-zygotic mutations contribute little to the human germ-line mutation rate. We find frequent recurrence of mutations at polymorphic CpG sites, and an increase in C to T mutations in a 5' CCG 3' to 5' CTG 3' context in the Pakistani population compared to Europeans, suggesting that mutational processes have evolved rapidly between human populations.Estimates of human mutation rates differ substantially based on the approach. Here, the authors present a multi-generational estimate from the autozygous segment in a non-European population that gives insight into the contribution of post-zygotic mutations and population-specific mutational processes.
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http://dx.doi.org/10.1038/s41467-017-00323-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566399PMC
August 2017

Continuity and Admixture in the Last Five Millennia of Levantine History from Ancient Canaanite and Present-Day Lebanese Genome Sequences.

Am J Hum Genet 2017 Aug 27;101(2):274-282. Epub 2017 Jul 27.

Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK. Electronic address:

The Canaanites inhabited the Levant region during the Bronze Age and established a culture that became influential in the Near East and beyond. However, the Canaanites, unlike most other ancient Near Easterners of this period, left few surviving textual records and thus their origin and relationship to ancient and present-day populations remain unclear. In this study, we sequenced five whole genomes from ∼3,700-year-old individuals from the city of Sidon, a major Canaanite city-state on the Eastern Mediterranean coast. We also sequenced the genomes of 99 individuals from present-day Lebanon to catalog modern Levantine genetic diversity. We find that a Bronze Age Canaanite-related ancestry was widespread in the region, shared among urban populations inhabiting the coast (Sidon) and inland populations (Jordan) who likely lived in farming societies or were pastoral nomads. This Canaanite-related ancestry derived from mixture between local Neolithic populations and eastern migrants genetically related to Chalcolithic Iranians. We estimate, using linkage-disequilibrium decay patterns, that admixture occurred 6,600-3,550 years ago, coinciding with recorded massive population movements in Mesopotamia during the mid-Holocene. We show that present-day Lebanese derive most of their ancestry from a Canaanite-related population, which therefore implies substantial genetic continuity in the Levant since at least the Bronze Age. In addition, we find Eurasian ancestry in the Lebanese not present in Bronze Age or earlier Levantines. We estimate that this Eurasian ancestry arrived in the Levant around 3,750-2,170 years ago during a period of successive conquests by distant populations.
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http://dx.doi.org/10.1016/j.ajhg.2017.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544389PMC
August 2017

Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations.

Nat Commun 2017 06 23;8:15927. Epub 2017 Jun 23.

The Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.

The genetic features of isolated populations can boost power in complex-trait association studies, and an in-depth understanding of how their genetic variation has been shaped by their demographic history can help leverage these advantageous characteristics. Here, we perform a comprehensive investigation using 3,059 newly generated low-depth whole-genome sequences from eight European isolates and two matched general populations, together with published data from the 1000 Genomes Project and UK10K. Sequencing data give deeper and richer insights into population demography and genetic characteristics than genotype-chip data, distinguishing related populations more effectively and allowing their functional variants to be studied more fully. We demonstrate relaxation of purifying selection in the isolates, leading to enrichment of rare and low-frequency functional variants, using novel statistics, DVxy and SVxy. We also develop an isolation-index (Isx) that predicts the overall level of such key genetic characteristics and can thus help guide population choice in future complex-trait association studies.
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http://dx.doi.org/10.1038/ncomms15927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490002PMC
June 2017

"Like sugar in milk": reconstructing the genetic history of the Parsi population.

Genome Biol 2017 06 14;18(1):110. Epub 2017 Jun 14.

CSIR - Centre for Cellular and Molecular Biology, Hyderabad, 500007, India.

Background: The Parsis are one of the smallest religious communities in the world. To understand the population structure and demographic history of this group in detail, we analyzed Indian and Pakistani Parsi populations using high-resolution genetic variation data on autosomal and uniparental loci (Y-chromosomal and mitochondrial DNA). Additionally, we also assayed mitochondrial DNA polymorphisms among ancient Parsi DNA samples excavated from Sanjan, in present day Gujarat, the place of their original settlement in India.

Results: Among present-day populations, the Parsis are genetically closest to Iranian and the Caucasus populations rather than their South Asian neighbors. They also share the highest number of haplotypes with present-day Iranians and we estimate that the admixture of the Parsis with Indian populations occurred ~1,200 years ago. Enriched homozygosity in the Parsi reflects their recent isolation and inbreeding. We also observed 48% South-Asian-specific mitochondrial lineages among the ancient samples, which might have resulted from the assimilation of local females during the initial settlement. Finally, we show that Parsis are genetically closer to Neolithic Iranians than to modern Iranians, who have witnessed a more recent wave of admixture from the Near East.

Conclusions: Our results are consistent with the historically-recorded migration of the Parsi populations to South Asia in the 7th century and in agreement with their assimilation into the Indian sub-continent's population and cultural milieu "like sugar in milk". Moreover, in a wider context our results support a major demographic transition in West Asia due to the Islamic conquest.
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http://dx.doi.org/10.1186/s13059-017-1244-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470188PMC
June 2017

The Connection of the Genetic, Cultural and Geographic Landscapes of Transoxiana.

Sci Rep 2017 06 8;7(1):3085. Epub 2017 Jun 8.

Research Centre for Medical Genetics, Moscow, Russia.

We have analyzed Y-chromosomal variation in populations from Transoxiana, a historical region covering the southwestern part of Central Asia. We studied 780 samples from 10 regional populations of Kazakhs, Uzbeks, Turkmens, Dungans, and Karakalpaks using 35 SNP and 17 STR markers. Analysis of haplogroup frequencies using multidimensional scaling and principal component plots, supported by an analysis of molecular variance, showed that the geographic landscape of Transoxiana, despite its distinctiveness and diversity (deserts, fertile river basins, foothills and plains) had no strong influence on the genetic landscape. The main factor structuring the gene pool was the mode of subsistence: settled agriculture or nomadic pastoralism. Investigation of STR-based clusters of haplotypes and their ages revealed that cultural and demic expansions of Transoxiana were not closely connected with each other. The Arab cultural expansion introduced Islam to the region but did not leave a significant mark on the pool of paternal lineages. The Mongol expansion, in contrast, had enormous demic success, but did not impact cultural elements like language and religion. The genealogy of Muslim missionaries within the settled agricultural communities of Transoxiana was based on spiritual succession passed from teacher to disciple. However, among Transoxianan nomads, spiritual and biological succession became merged.
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http://dx.doi.org/10.1038/s41598-017-03176-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465200PMC
June 2017