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Copy number variants (CNVs) represent major etiologic factors in rare genetic diseases. Current clinical CNV interpretation workflows require extensive back-and-forth with multiple tools and databases. This increases complexity and time burden, potentially resulting in missed genetic diagnoses. We present the Suite for CNV Interpretation and Prioritization (SCIP), a software package for the clinical interpretation of CNVs detected by whole-genome sequencing (WGS). The SCIP Visualization Module near-instantaneously displays all information necessary for CNV interpretation (variant quality, population frequency, inheritance pattern, and clinical relevance) on a single page—supported by modules providing variant filtration and prioritization. SCIP was comprehensively evaluated using WGS data from 1027 families with congenital cardiac disease and/or autism spectrum disorder, containing 187 pathogenic or likely pathogenic (P/LP) CNVs identified in previous curations. SCIP was efficient in filtration and prioritization: a median of just two CNVs per case were selected for review, yet it captured all P/LP findings (92.5% of which ranked 1st). SCIP was also able to identify one pathogenic CNV previously missed. SCIP was benchmarked against AnnotSV and a spreadsheet-based manual workflow and performed superiorly than both. In conclusion, SCIP is a novel software package for efficient clinical CNV interpretation, substantially faster and more accurate than previous tools (available at https://github.com/qd29/SCIP, a video tutorial series is available at https://bit.ly/SCIPVideos).

Funder: National Institute of Health (NIH) DP2-GM123495, DNA replication follows a strict spatiotemporal program that intersects with chromatin structure but has a poorly understood genetic basis. To systematically identify genetic regulators of replication timing, we exploited inter-individual variation in human pluripotent stem cells from 349 individuals. We show that the human genome���s replication program is broadly encoded in DNA and identify 1,617 cis-acting replication timing quantitative trait loci (rtQTLs) ��� sequence determinants of replication initiation. rtQTLs function individually, or in combinations of proximal and distal regulators, and are enriched at sites of histone H3 trimethylation of lysines 4, 9, and 36 together with histone hyperacetylation. H3 trimethylation marks are individually repressive yet synergistically associate with early replication. We identify pluripotency-related transcription factors and boundary elements as positive and negative regulators of replication timing, respectively. Taken together, human replication timing is controlled by a multi-layered mechanism with dozens of effectors working combinatorially and following principles analogous to transcription regulation.

DNA is replicated according to a defined spatiotemporal program that is linked to both gene regulation and genome stability. The evolutionary forces that have shaped replication timing programs in eukaryotic species are largely unknown. Here, we studied the molecular causes and consequences of replication timing evolution across 94 humans, 95 chimpanzees, and 23 rhesus macaques. Replication timing differences recapitulated the species’ phylogenetic tree, suggesting continuous evolution of the DNA replication timing program in primates. Hundreds of genomic regions had significant replication timing variation between humans and chimpanzees, of which 66 showed advances in replication origin firing in humans while 57 were delayed. Genes overlapping these regions displayed correlated changes in expression levels and chromatin structure. Many human-chimpanzee variants also exhibited inter-individual replication timing variation, pointing to ongoing evolution of replication timing at these loci. Association of replication timing variation with genetic variation revealed that DNA sequence evolution can explain replication timing variation between species. Taken together, DNA replication timing shows substantial and ongoing evolution in the human lineage that is driven by sequence alterations and impacts regulatory evolution.

Fully understanding autism spectrum disorder (ASD) genetics requires whole-genome sequencing (WGS). We present the latest release of the Autism Speaks MSSNG resource, which includes WGS data from 5,100 individuals with ASD and 6,212 non-ASD parents and siblings (total n = 11,312). Examining a wide variety of genetic variants in MSSNG and the Simons Simplex Collection (SSC; n = 9,205), we identified ASD-associated rare variants in 718/5,100 individuals with ASD from MSSNG (14.1%) and 350/2,419 from SSC (14.5%). Considering genomic architecture, 52% were nuclear sequence-level variants, 46% were nuclear structural variants (including copy-number variants, inversions, large insertions, uniparental isodisomies, and tandem repeat expansions), and 2% were mitochondrial variants. Our study provides a guidebook for exploring genotype-phenotype correlations in families who carry ASD-associated rare variants and serves as an entry point to the expanded studies required to dissect the etiology in the ∼85% of the ASD population that remain idiopathic.

Haploid human embryonic stem cells (ESCs) provide a powerful genetic system but diploidize at high rates. We hypothesized that diploidization results from aberrant DNA replication. To test this, we profiled DNA replication timing in isogenic haploid and diploid ESCs. The greatest difference was the earlier replication of the X Chromosome in haploids, consistent with the lack of X-Chromosome inactivation. We also identified 21 autosomal regions that had delayed replication in haploids, extending beyond the normal S phase and into G2/M. Haploid-delays comprised a unique set of quiescent genomic regions that are also underreplicated in polyploid placental cells. The same delays were observed in female ESCs with two active X Chromosomes, suggesting that increased X-Chromosome dosage may cause delayed autosomal replication. We propose that incomplete replication at the onset of mitosis could prevent cell division and result in re-entry into the cell cycle and whole genome duplication.

A common assumption in dating patrilineal events using Y-chromosome sequencing data is that the Y-chromosome mutation rate is invariant across haplogroups. Previous studies revealed interhaplogroup heterogeneity in phylogenetic branch length. Whether this heterogeneity is caused by interhaplogroup mutation rate variation or nongenetic confounders remains unknown. Here, we analyzed whole-genome sequences from cultured cells derived from >1,700 males. We confirmed the presence of branch length heterogeneity. We demonstrate that sex-chromosome mutations that appear within cell lines, which likely occurred somatically or in vitro (and are thus not influenced by nongenetic confounders) are informative for germline mutational processes. Using within-cell-line mutations, we computed a relative Y-chromosome somatic mutation rate, and uncovered substantial variation (up to 83.3%) in this proxy for germline mutation rate among haplogroups. This rate positively correlates with phylogenetic branch length, indicating that interhaplogroup mutation rate variation is a likely cause of branch length heterogeneity.

DNA replication follows a strict spatiotemporal program that intersects with chromatin structure and gene regulation. However, the genetic basis of the mammalian DNA replication timing program is poorly understood1–3. To systematically identify genetic regulators of DNA replication timing, we exploited inter-individual variation in 457 human pluripotent stem cell lines from 349 individuals. We show that the human genome’s replication program is broadly encoded in DNA and identify 1,617 cis-acting replication timing quantitative trait loci (rtQTLs4) – base-pair-resolution sequence determinants of replication initiation. rtQTLs function individually, or in combinations of proximal and distal regulators, to affect replication timing. Analysis of rtQTL locations reveals a histone code for replication initiation, composed of bivalent histone H3 trimethylation marks on a background of histone hyperacetylation. The H3 trimethylation marks are individually repressive yet synergize to promote early replication. We further identify novel positive and negative regulators of DNA replication timing, the former comprised of pluripotency-related transcription factors while the latter involve boundary elements. Human replication timing is controlled by a multi-layered mechanism that operates on target DNA sequences, is composed of dozens of effectors working combinatorially, and follows principles analogous to transcription regulation: a histone code, activators and repressors, and a promoter-enhancer logic.

The origin of Tibetans remains one of the most contentious puzzles in history, anthropology, and genetics. Analyses of deeply sequenced (30×–60×) genomes of 38 Tibetan highlanders and 39 Han Chinese lowlanders, together with available data on archaic and modern humans, allow us to comprehensively characterize the ancestral makeup of Tibetans and uncover their origins. Non-modern human sequences compose ∼6% of the Tibetan gene pool and form unique haplotypes in some genomic regions, where Denisovan-like, Neanderthal-like, ancient-Siberian-like, and unknown ancestries are entangled and elevated. The shared ancestry of Tibetan-enriched sequences dates back to ∼62,000–38,000 years ago, predating the Last Glacial Maximum (LGM) and representing early colonization of the plateau. Nonetheless, most of the Tibetan gene pool is of modern human origin and diverged from that of Han Chinese ∼15,000 to ∼9,000 years ago, which can be largely attributed to post-LGM arrivals. Analysis of ∼200 contemporary populations showed that Tibetans share ancestry with populations from East Asia (∼82%), Central Asia and Siberia (∼11%), South Asia (∼6%), and western Eurasia and Oceania (∼1%). Our results support that Tibetans arose from a mixture of multiple ancestral gene pools but that their origins are much more complicated and ancient than previously suspected. We provide compelling evidence of the co-existence of Paleolithic and Neolithic ancestries in the Tibetan gene pool, indicating a genetic continuity between pre-historical highland-foragers and present-day Tibetans. In particular, highly differentiated sequences harbored in highlanders’ genomes were most likely inherited from pre-LGM settlers of multiple ancestral origins (SUNDer) and maintained in high frequency by natural selection.

Skin color is one of the most visible and important phenotypes of modern humans. Melanocyte-stimulating hormone and its receptor played an important role in regulating skin color. In this article, we present evidence of Neanderthal introgression encompassing the melanocyte-stimulating hormone receptor gene MC1R. The haplotypes from Neanderthal introgression diverged with the Altai Neanderthal 103.3 ka, which postdates the anatomically modern human-Neanderthal divergence. We further discovered that all of the putative Neanderthal introgressive haplotypes carry the Val92Met variant, a loss-of-function variant in MC1R that is associated with multiple dermatological traits including skin color and photoaging. Frequency of this Neanderthal introgression is low in Europeans (∼5%), moderate in continental East Asians (∼30%), and high in Taiwanese aborigines (60-70%). As the putative Neanderthal introgressive haplotypes carry a loss-of-function variant that could alter the function of MC1R and is associated with multiple traits related to skin color, we speculate that the Neanderthal introgression may have played an important role in the local adaptation of Eurasians to sunlight intensity.

A growth trial was conducted to detect the effects of different diets on the growth performance and hypoxia adaptation capacity of Mississippi Paddlefish (Polyodon spathula) larvae. The larvae were fed with live food, formulated diets, and 1/2 live food with 1/2 formulated diets. After a 15-d growth trial, final body weight and total body length were measured, and five larvae from each dietary group were subjected to 1 h of hypoxia treatment. Serum total antioxidant capacity (T-AOC), serum superoxide dismutase (SOD), and liver malondialdehyde (MDA) were measured. Final body weight and weight gain of the fish fed live food were significantly higher than the values for the other two groups. Total body length of the fish fed live food and 1/2 live food with 1/2 formulated diets exhibited no significant difference. After hypoxia treatment, serum T-AOC and SOD activities of the fish fed formulated diets were significantly lower than those of the other two groups. Liver MDA content of the fish fed with live food was significantly higher than that of the other two groups. In conclusion, larval paddlefish fed with an appropriate proportion of live food and formulated diets exhibit improved adaptive capacity to hypoxia.

Y chromosome haplogroup O3-M122 is the most prevalent haplogroup in East Asia, and provides an ideal tool for dissecting primary dispersals of the East Asians. Most of the sub-haplogroups of O3-M122 have been sufficiently investigated except for O3a1c-002611, despite its great prevalence and huge population, especially in Han Chinese. In this study, we identified 508 individuals with haplogroup O3a1c-002611 out of 7801 males from 117 East and Southeast Asian populations, typed at two newly discovered downstream Y-SNP markers and ten commonly used Y-STRs. Defined by SNPs IMS-JST002611 (in short, 002611), F11, and F238, three lineages internal to haplogroup O3a1c-002611 have distinct geographical distributions. Furthermore, Y-STR diversity shows a general south-to-north decline, which is consistent with the prehistorically northward migration of the other O3-M122 lineages. The northward migration of haplogroup O3a1c-002611 started about 13 thousand years ago (KYA). The expansions of subclades F11 and F238 in ancient Han Chinese began about 5 and 7 KYA immediately after the separation between the ancestors of the Han Chinese and Tibeto-Burman.

The Japanese people are one of the most important populations for studying the origin and diversification of East Asian populations. As an island population, the Japanese's path of migration is a long-standing controversy. Archeological evidence suggests that there were at least two waves of migration to the Japanese archipelago in prehistory: the Paleolithic and Neolithic Jomonese as well as the Aeneolithic Yayoiese. However, the contributions of these Jomonese and Yayoiese to the contemporary Japanese population remain unclear. In this article, we provide evidence from human genetics as a new approach to addressing this topic. At the beginning, we introduce the history of human migration to the Japanese archipelago, as well as materials and methods human geneticists use. Subsequently, we tested three distinct population expansion models using evidences from recent human genetic studies on the Japanese, East Asian, and Serbian populations. Finally, we conclude that the contemporary main island Japanese are the result of population admixture of Jomonese, Yayoiese, and Han Chinese, which consists with the Admixture model.

In this study, we present an analysis of Neanderthal introgression at the dipeptidase 1 gene, DPEP1. A Neanderthal origin for the putative introgressive haplotypes was demonstrated using an established three-step approach. This introgression was under positive natural selection, reached a frequency of >50%, and introduced a homocysteine level- and pigmentation-associated allele (rs460879-T) into East Asians. However, the same allele was also found in non-East Asians, but not from Neanderthal introgression. It is likely that rs460879-T was lost in East Asians and was reintroduced subsequently through Neanderthal introgression. Our findings suggest that Neanderthal introgression could reintroduce an important previously existing allele into populations where the allele had been lost. This study sheds new light on understanding the contribution of Neanderthal introgression to the adaptation of non-Africans.

Previous research reported that Papua New Guineans (PNG) and Australians contain introgressions from Denisovans. Here we present a genome-wide analysis of Denisovan introgressions in PNG and Australians. We firstly developed a two-phase method to detect Denisovan introgressions from whole-genome sequencing data. This method has relatively high detection power (79.74%) and low false positive rate (2.44%) based on simulations. Using this method, we identified 1.34 Gb of Denisovan introgressions from sixteen PNG and four Australian genomes, in which we identified 38,877 Denisovan introgressive alleles (DIAs). We found that 78 Denisovan introgressions were under positive selection. Genes located in the 78 introgressions are related to evolutionarily important functions, such as spermatogenesis, fertilization, cold acclimation, circadian rhythm, development of brain, neural tube, face, and olfactory pit, immunity, etc. We also found that 121 DIAs are missense. Genes harboring the 121 missense DIAs are also related to evolutionarily important functions, such as female pregnancy, development of face, lung, heart, skin, nervous system, and male gonad, visual and smell perception, response to heat, pain, hypoxia, and UV, lipid transport, metabolism, blood coagulation, wound healing, aging, etc. Taken together, this study suggests that Denisovan introgressions in PNG and Australians are evolutionarily important, and may help PNG and Australians in local adaptation. In this study, we also proposed a method that could efficiently identify archaic hominin introgressions in modern non-African genomes.

Studies of the Neanderthal and Denisovan genomes demonstrate archaic hominin introgression in Eurasians. Here, we present evidence of Neanderthal introgression within the chromosome 3p21.31 region, occurring with a high frequency in East Asians (ranging from 49.4% to 66.5%) and at a low frequency in Europeans. We also detected a signal of strong positive selection in this region only in East Asians. Our data indicate that likely candidate targets of selection include rs12488302-T and its associated alleles--among which four are nonsynonymous, including rs35455589-G in HYAL2, a gene related to the cellular response to ultraviolet-B irradiation. Furthermore, suggestive evidence supports latitude-dependent selection, implicating a role of ultraviolet-B. Interestingly, the distribution of rs35455589-G suggests that this allele was lost during the exodus of ancestors of modern Eurasians from Africa and reintroduced to Eurasians from Neanderthals.

Temme et al. (1) found that the Neanderthals and the HLA-DPB1*0401 shared Lys at the 69th amino acid and GGPM at the 84th to 87th amino acids of HLA-DPβ. They thus concluded that the Lys-69/GGPM-(84–87) in DPB1*0401 was derived from a Neanderthal introgression. They observed that DPB1*0401 is rare in sub-Saharan Africans (SSA), which is consistent with the claim that the DPB1*0401 was from Neanderthal introgression. However, the DPB1*0402 also carries the Lys-69/GGPM-(84–87), and the frequency of DPB1*0401 and DPB1*0402 in SSA are 5.5 and 18.9%, respectively. Given that the SSA are nearly free from Neanderthal introgression (2), it is less likely that haplotypes from Neanderthal could reach a frequency as high as 24.4% in SSA. Further, we reconstructed a phylogenetic tree for DPB1*0201, DPB1*0202, DPB1*0301, DPB1*0401, and DPB1*0402 haplotypes, along with chimpanzee and high coverage Neanderthal and Denisovan sequences. If the DPB1*0401 were from recent Neanderthal introgression, one would expect that it first coalesced with Neanderthal, instead of other modern human haplotypes (3). However, it was observed that the DPB1*0401 first coalesced with DPB1*0402, then with the two DPB1*02 haplotypes, and then with the Neanderthal and Denisovan sequences. Divergence time between DPB1*0401 and Neanderthal was estimated as 2200 thousand years ago (KYA) (95% confidence interval (CI): 1657.8–2742.2 KYA), which far predates the Neanderthal − modern human divergence time (∼270 KYA). This observation is also inconsistent with the hypothesis that the DPB1*0401 was from Neanderthal introgression. To summarize, the identified Neanderthal introgression at HLA-DPB1*0401 could be an artifact that resulted from ancient population structure.

Atkinson (Reports, 15 April 2011, p. 346) reported a declined trend of phonemic diversity from Africa that indicated the African exodus of modern languages. However, his claim was only supported when the phonemic diversities were binned into three or five levels. Analyses using raw data without simplification suggest a decline from central Asia rather than from Africa.