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Interpretations of genetic data concerning the prehistory of Europe have long been a subject of great debate, but increasing amounts of ancient and modern DNA data are now providing new and more informative evidence. Y-chromosome resequencing studies in Europe have highlighted the prevalence of recent expansions of male lineages, and focused interest on the Bronze Age as a period of cultural and demographic change. These findings contrast with phylogeographic studies based on mitochondrial DNA (mtDNA), which have been interpreted as supporting expansions from glacial refugia. Here we have undertaken a population-based resequencing of complete mitochondrial genomes in Europe and the Middle East, in 340 samples from 17 populations for which Y-chromosome sequence data are also available. Demographic reconstructions show no signal of Bronze Age expansion, but evidence of Paleolithic expansions in all populations except the Saami, and with an absence of detectable geographical pattern. In agreement with previous inference from modern and ancient DNA data, the unbiased comparison between the mtDNA and Y-chromosome population datasets emphasizes the sex-biased nature of recent demographic transitions in Europe.

Objective:\ud The male-specific region of the Y chromosome (MSY) remains one of the most unexplored regions of the genome. We sought to examine how the genetic variants of the MSY influence male susceptibility to coronary artery disease (CAD) and atherosclerosis.\ud \ud Approach and Results:\ud Analysis of 129 133 men from UK Biobank revealed that only one of 7 common MSY haplogroups (haplogroup I1) was associated with CAD—carriers of haplogroup I1 had ≈11% increase in risk of CAD when compared with all other haplogroups combined (odds ratio, 1.11; 95% CI, 1.04–1.18; P=6.8×10−4). Targeted MSY sequencing uncovered 235 variants exclusive to this haplogroup. The haplogroup I1–specific variants showed 2.45- and 1.56-fold respective enrichment for promoter and enhancer chromatin states, in cells/tissues relevant to atherosclerosis, when compared with other MSY variants. Gene set enrichment analysis in CAD-relevant tissues showed that haplogroup I1 was associated with changes in pathways responsible for early and late stages of atherosclerosis development including defence against pathogens, immunity, oxidative phosphorylation, mitochondrial respiration, lipids, coagulation, and extracellular matrix remodeling. UTY was the only Y chromosome gene whose blood expression was associated with haplogroup I1. Experimental reduction of UTY expression in macrophages led to changes in expression of 59 pathways (28 of which overlapped with those associated with haplogroup I1) and a significant reduction in the immune costimulatory signal.\ud \ud Conclusions:\ud Haplogroup I1 is enriched for regulatory chromatin variants in numerous cells of relevance to CAD and increases cardiovascular risk through proatherosclerotic reprogramming of the transcriptome, partly through UTY.

Additional file 2: Supplementary notes for breakpoint identification. (PDF 4747 kb)

The distribution of genetic diversity in great ape species is likely to have been affected by patterns of dispersal and mating. This has previously been investigated by sequencing autosomal and mitochondrial DNA (mtDNA), but large-scale sequence analysis of the male-specific region of the Y Chromosome (MSY) has not yet been undertaken. Here, we use the human MSY reference sequence as a basis for sequence capture and read mapping in 19 great ape males, combining the data with sequences extracted from the published whole genomes of 24 additional males to yield a total sample of 19 chimpanzees, four bonobos, 14 gorillas, and six orangutans, in which interpretable MSY sequence ranges from 2.61 to 3.80 Mb. This analysis reveals thousands of novel MSY variants and defines unbiased phylogenies. We compare these with mtDNA-based trees in the same individuals, estimating time-to-most-recent common ancestor (TMRCA) for key nodes in both cases. The two loci show high topological concordance and are consistent with accepted (sub)species definitions, but time depths differ enormously between loci and (sub)species, likely reflecting different dispersal and mating patterns. Gorillas and chimpanzees/bonobos present generally low and high MSY diversity, respectively, reflecting polygyny versus multimale-multifemale mating. However, particularly marked differences exist among chimpanzee subspecies: The western chimpanzee MSY phylogeny has a TMRCA of only 13.2 (10.8-15.8) thousand years, but that for central chimpanzees exceeds 1 million years. Cross-species comparison within a single MSY phylogeny emphasizes the low human diversity, and reveals species-specific branch length variation that may reflect differences in long-term generation times.

Duplications of genetic material have been considered as a key mechanism leading to the rise of new genes and biological processes in the course of evolution. Duplications are important in generating both inter- and intra-specific variations, and are prone to non-homologous recombination and gene conversion. One of the gene families that has evolved through duplication events in the primate lineage is the Luteinizing hormone/ Chorionic Gonadotropin beta-subunit (LHB/CGB) genome cluster. LHB/CGB genes encode for the beta subunit of gonadotropin hormones having an essential role in reproduction and fertility. Current study showed that duplicated and highly identical LHB/CGB genes have up to 7x higher diversity in human populations (Estonians, Chinese Han, African Mandenkalu) com-pared to unique genes. High sequence variation and strong LD are co-localized in genes showing evidence of gene conversion acceptor activity. Gene conversion donor genes exhibit lower diversity and breakdown of LD. Comparison of human and chimpanzee LHB/CGB genome clusters revealed independent duplication events in these species resulting in discordant number of CGB genes (6 in human and 5 in chimpanzee). Active gene conversion may have contributed to higher interspecific sequence divergence and altered transition/transversion ratio compared to single-copy loci. Despite the high sequence identity, the individual LHB/CGB genes might be evolving under different selective constraints. Study of CGB1/CGB2-like genes in human, chimpanzee, gorilla and orangutan indicated that these genes may have arisen in the common ancestor of African great apes and might be functional genes in human and chimpanzee. The results indicate the important role of gene conversion in the evolution of duplicated regions and active dynamics of LHB/CGB genomic region. Geneetilise materjali duplikatsioone peetakse üheks peamiseks evolutsiooni mehhanismiks, olles uute geenide ja bioloogiliste protsesside tekkimise aluseks. Duplikatsioonid on olulised nii liikide vaheliste kui liikide siseste geneetiliste ja fenotüübiliste varieeruvuste tekitajad. Sellised kõrge DNA järjestuse homoloogiaga alad on altid mitte-homoloogilisele rekombinat-sioonile ja geenikonversioonile. Üheks primaatide liinis duplikatsioonide tagajärjel tekkinud geeniperekonnaks on Luteiniseeriva hormooni/ Koorion Gonadotropiini beeta-subühiku (LHB/CGB) geeniklaster. LHB/CGB geenid kodeerivad gonadotroopisete hormoonide beeta subühikuid, mis on asendamatud normaalse viljakuse tagamisel. Käesolevas töös leiti, et inimpopulatsioonis (Eesti, Hiina Han, Aafrika Mandenkalu) on dup-litseeritud LHB/CGB geenide DNA järjestuse varieeruvus kuni 7x kõrgem võrreldes uni-kaalsete geenidega. Kõrge DNA varieeruvus ja tugev alleelne assotsiatsioon iseloomustavad geenikonversioonis aktseptoritena osalevaid geene, geenikonversiooni doonorite varieeruvus ja alleelse assotsiatsiooni ulatus on madalamad. Inimese ja šimpansi LHB/CGB genoomi-klastrite võrdlusel selgus, et mõlemas liigis toimunud sõltumatud duplikatsioonid on põhjus-tanud erinevuse CGB geenide koopiaarvus (inimesel 6, šimpansil 5 CGB geeni). Unikaal-setest regioonidest kõrgem divergents ja muutunud transitsioonide/transversioonide suhe on ilmselt aktiivse geenikonversiooni toimumise tagajärg. Kuigi LHB/CGB geenid on DNA järjestuselt omavahel väga sarnased, võib üksikute geenide evolutsioon toimuda erinevat tüüpi loodusliku valiku survete all. CGB1-CGB2-sarnaste geenide uurimine inimesel, šimpansil, gorillal ja orangutanil viitab, et need geenid on tekkinud evolutsiooni mastaabis suhteliselt hiljuti, ilmselt Aafrika inimahvide ühisel eellasel ning inimesel ja šimpansil võib olla tegemist funktsionaalsete geenidega. Antud töö tulemused viitavad geenikonversiooni olulisele rollile duplitseerunud genoomipiirkondade evolutsioonis ning LHB/CGB geeniklastri aktiivsele dünaamikale.