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Key Points As a consequence of its key role in male sex determination, the Y chromosome has unique genetic properties that lead to it carrying highly informative haplotypes that evolve largely through the simple accumulation of mutations. Advances in technology have allowed ~10 Mb of Y-chromosome DNA to be sequenced from large population samples, with consequent unbiased ascertainment of their genetic variation. Y-Chromosome sequences can be assembled into a robust phylogeny, which can be calibrated using estimates of the mutation rate from family studies, known archaeological events or ancient DNA samples. The calibrated Y-chromosome phylogeny reveals male expansions corresponding to the migration of modern humans out of Africa ~60,000 years ago, the colonization of the Americas ~15,000 years ago and more recent technology-driven population expansions. The Y chromosome has a particularly important role in forensic genetics, as it allows male-specific DNA profiles to be compared at an increasingly high resolution. In genealogical studies, the male-line inheritance of the Y chromosome makes it a perfect tool for studies of male family history, which has led to a burgeoning area of citizen science. The Y chromosome is central to disorders of sex determination and spermatogenesis. Recently, mosaic somatic loss of the Y chromosome in ageing men has been associated with an increased risk of cancer mortality and Alzheimer disease. Genetic variation of the human Y chromosome plays a key part in studies of human evolution, population history, genealogy, forensics and male medical genetics. This Review outlines how next-generation sequencing has contributed to recent progress in these fields. The properties of the human Y chromosome – namely, male specificity, haploidy and escape from crossing over — make it an unusual component of the genome, and have led to its genetic variation becoming a key part of studies of human evolution, population history, genealogy, forensics and male medical genetics. Next-generation sequencing (NGS) technologies have driven recent progress in these areas. In particular, NGS has yielded direct estimates of mutation rates, and an unbiased and calibrated molecular phylogeny that has unprecedented detail. Moreover, the availability of direct-to-consumer NGS services is fuelling a rise of 'citizen scientists', whose interest in resequencing their own Y chromosomes is generating a wealth of new data.

Mike Stratton and colleague show that carriers of a germline copy number polymorphism involving APOBEC3A and APOBEC3B , which has been associated with increased risk of breast cancer, show more mutations characteristic of APOBEC-dependent mutational processes than cancers in non-carriers. The somatic mutations in a cancer genome are the aggregate outcome of one or more mutational processes operative through the lifetime of the individual with cancer 1 , 2 , 3 . Each mutational process leaves a characteristic mutational signature determined by the mechanisms of DNA damage and repair that constitute it. A role was recently proposed for the APOBEC family of cytidine deaminases in generating particular genome-wide mutational signatures 1 , 4 and a signature of localized hypermutation called kataegis 1 , 4 . A germline copy number polymorphism involving APOBEC3A and APOBEC3B , which effectively deletes APOBEC3B 5 , has been associated with modestly increased risk of breast cancer 6 , 7 , 8 . Here we show that breast cancers in carriers of the deletion show more mutations of the putative APOBEC-dependent genome-wide signatures than cancers in non-carriers. The results suggest that the APOBEC3A - APOBEC3B germline deletion allele confers cancer susceptibility through increased activity of APOBEC-dependent mutational processes, although the mechanism by which this increase in activity occurs remains unknown.

Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterization of African genetic diversity is needed. The African Genome Variation Project provides a resource with which to design, implement and interpret genomic studies in sub-Saharan Africa and worldwide. The African Genome Variation Project represents dense genotypes from 1,481 individuals and whole-genome sequences from 320 individuals across sub-Saharan Africa. Using this resource, we find novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa. We identify new loci under selection, including loci related to malaria susceptibility and hypertension. We show that modern imputation panels (sets of reference genotypes from which unobserved or missing genotypes in study sets can be inferred) can identify association signals at highly differentiated loci across populations in sub-Saharan Africa. Using whole-genome sequencing, we demonstrate further improvements in imputation accuracy, strengthening the case for large-scale sequencing efforts of diverse African haplotypes. Finally, we present an efficient genotype array design capturing common genetic variation in Africa. The African Genome Variation Project contains the whole-genome sequences of 320 individuals and dense genotypes on 1,481 individuals from sub-Saharan Africa; it enables the design and interpretation of genomic studies, with implications for finding disease loci and clues to human origins. Genetic variation in sub-Saharan Africa The African Genome Variation Project (AGVP) is collecting data on the structure of African genomes to provide a central resource for genetic disease studies in Africa. It currently represents dense genotypes from 1,481 individuals and whole-genome sequences from 320 individuals across sub-Saharan Africa. Using these data, Manjinder Sandhu and colleagues identify new loci under selection, including those associated with malaria and hypertension. They show that modern imputation panels can identify association signals at highly differentiated loci across population groups. They demonstrate the utility of whole-genome sequences in further improving the imputation accuracy. In addition, they describe the first efficient genotype array design capturing common genetic variation in Africa.

British population history has been shaped by a series of immigrations, including the early Anglo-Saxon migrations after 400 CE. It remains an open question how these events affected the genetic composition of the current British population. Here, we present whole-genome sequences from 10 individuals excavated close to Cambridge in the East of England, ranging from the late Iron Age to the middle Anglo-Saxon period. By analysing shared rare variants with hundreds of modern samples from Britain and Europe, we estimate that on average the contemporary East English population derives 38% of its ancestry from Anglo-Saxon migrations. We gain further insight with a new method, rarecoal, which infers population history and identifies fine-scale genetic ancestry from rare variants. Using rarecoal we find that the Anglo-Saxon samples are closely related to modern Dutch and Danish populations, while the Iron Age samples share ancestors with multiple Northern European populations including Britain. This study examines ancient genomes of individuals from the late Iron Age to the middle Anglo-Saxon period in the East of England. Using a newly devised analytic algorithm, the author also estimate the relative ancestry of East English genome derived from Anglo-Saxon migrations and to the rest of Europe.

Mountain gorillas are an endangered great ape subspecies and a prominent focus for conservation, yet we know little about their genomic diversity and evolutionary past. We sequenced whole genomes from multiple wild individuals and compared the genomes of all four Gorilla subspecies. We found that the two eastern subspecies have experienced a prolonged population decline over the past 100,000 years, resulting in very low genetic diversity and an increased overall burden of deleterious variation. A further recent decline in the mountain gorilla population has led to extensive inbreeding, such that individuals are typically homozygous at 34% of their sequence, leading to the purging of severely deleterious recessive mutations from the population. We discuss the causes of their decline and the consequences for their future survival.

Structural variations of DNA greater than 1 kilobase in size account for most bases that vary among human genomes, but are still relatively under-ascertained. Here we use tiling oligonucleotide microarrays, comprising 42 million probes, to generate a comprehensive map of 11,700 copy number variations (CNVs) greater than 443 base pairs, of which most (8,599) have been validated independently. For 4,978 of these CNVs, we generated reference genotypes from 450 individuals of European, African or East Asian ancestry. The predominant mutational mechanisms differ among CNV size classes. Retrotransposition has duplicated and inserted some coding and non-coding DNA segments randomly around the genome. Furthermore, by correlation with known trait-associated single nucleotide polymorphisms (SNPs), we identified 30 loci with CNVs that are candidates for influencing disease susceptibility. Despite this, having assessed the completeness of our map and the patterns of linkage disequilibrium between CNVs and SNPs, we conclude that, for complex traits, the heritability void left by genome-wide association studies will not be accounted for by common CNVs. Major CNV data sets Copy number variations or CNVs are a common form of genetic variation between individuals, caused by genomic rearrangements, either inherited or due to de novo mutation. A major collaborative effort using tiling oligonucleotide microarrays and HapMap samples has generated a comprehensive working map of 11,700 CNVs in the human genome. About half of these were also genotyped in individuals of different ancestry — European, African or East Asian. Thirty loci with CNVs that are candidates for influencing disease susceptibility were identified. Published online last October, this vast data set is a landmark in terms of completeness and spatial resolution, and as John Armour wrote in News & Views , is likely to stand as a definitive resource for years to come. This resource is the main focus of a new genome-wide association study, from the Wellcome Trust Case Control Consortium, of the links between common CNVs and eight common human diseases. Providing a wealth of technical insights to inform future study design and analysis, the Wellcome study also implies that common CNVs that can be genotyped using existing platforms are unlikely to have a major role in the genetic basis of common diseases. Much genetic variation among humans can be accounted for by structural DNA differences that are greater than 1 kilobase in size. Here, using tiling oligonucleotide arrays and HapMap samples, a map of 11,700 copy number variations (CNVs) bigger than 443 base pairs has been generated. About half of these CNVs were also genotyped in individuals of different ancestry. The results offer insight into the relative prevalence of mechanisms that generate CNVs, their evolution, and their contribution to complex genetic diseases.

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.

Key Points The human Y chromosome is male-sex-determining and haploid, and so escapes recombination for most of its length. Haplotypes, which can be defined by the many binary markers and microsatellites that are available, pass down paternal lineages and change only by mutation. A small effective population size and the practice of patrilocality accentuate drift, which leads to the marked geographical differentiation of Y haplotypes. This makes the Y chromosome a powerful tool for investigating events in human genetic history. The study of mutation on the Y chromosome clarifies intra-allelic processes in general, and provides specific information about mutation rates that is useful in estimating the coalescent times of lineages. Intrachromosomal paralogous sequences are plentiful and cause pathogenic and non-pathogenic structural rearrangements. Selection might be important in shaping Y-chromosome diversity in populations, but it has been difficult to identify. Some studies show associations between deleterious phenotypes and particular haplotypes, but these associations are weak; some coalescence times are younger than expected, which indicates recent selection, but these estimates are uncertain, and population phenomena might be an alternative explanation. The phylogeny of binary Y haplogroups is well established, but the dates of branchpoints are uncertain. Many populations have been poorly sampled, and there is ascertainment bias in the set of available binary markers. The recent coalescence time, rooting of the Y phylogeny in Africa and evidence for an 'Out-of-Africa' range expansion, all show that modern Y-chromosome diversity arose recently in Africa and replaced Y chromosomes elsewhere. The pattern of Y-chromosome variation broadly fits a model of a southern migration that reached Australia, and a northern migration into Eurasia. Many features of the patterns of modern Y-chromosome diversity reflect later range expansions and contractions that were driven by changes in climate and lifestyle. Long-term population size, social structures and social selection have also been important. Future developments in the field are likely to include more markers, and a move towards the unbiased resequencing of samples. Other parts of the genome might show a 'haplotype-block' structure that is made up of regions of strong linkage disequilibrium. If this is so, then methods pioneered in the analysis of the Y chromosome could be widely applicable. Until recently, the Y chromosome seemed to fulfil the role of juvenile delinquent among human chromosomes — rich in junk, poor in useful attributes, reluctant to socialize with its neighbours and with an inescapable tendency to degenerate. The availability of the near-complete chromosome sequence, plus many new polymorphisms, a highly resolved phylogeny and insights into its mutation processes, now provide new avenues for investigating human evolution. Y-chromosome research is growing up.

Humans expanded out of Africa 50,000-70,000 years ago, but many details of this migration are poorly understood. Here, Haber et al. sequence Y chromosomes belonging to a rare African lineage and analyze... 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.

Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British adults of Pakistani heritage with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were linked to the individuals' lifelong health records, we observed no significant relationship between gene knockouts and clinical consultation or prescription rate. In this data set, we identified a healthy PRDM9-knockout mother and performed phased genome sequencing on her, her child, and control individuals. Our results show that meiotic recombination sites are localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform on essential genetic loci and demonstrate PRDM9 redundancy in humans.