Abstract

Pleiotropic and monotonic effects of gene dosage are central to understanding comorbidities in developmental pediatric and psychiatric disorders, yet the underlying biological processes are not well characterized. Here we develop a functional burden analysis to investigate the association of all protein-coding copy-number variants, genome-wide, with 43 complex traits in approximately 500,000 UK Biobank participants. We test variant associations disrupting 172 tissue or cell-type gene sets, finding associations for all traits, which we replicate in the All of Us cohort. Functional burden pleiotropy, defined as the number of traits significantly associated with a gene set, correlates with genetic constraint and is higher for brain than non-brain functions, even after normalizing for genetic constraint. Levels of pleiotropy, measured by burden correlation, are similar in deletions and loss-of-function single-nucleotide variants, and higher than in common variants and duplications. Most gene dosage responses are non-monotonic, with deletions and duplications showing same-direction effects, and monotonic responses decrease with genetic constraint. We observe associations between functional gene sets and traits for either deletions or duplications, but rarely both, with negatively correlated effect sizes. Together, these results link genetic constraint and brain-specific mechanisms to the whole-body multimorbidity of neurodevelopmental and psychiatric conditions.

Abstract

Forensic investigative genetic genealogy (FIGG) is a revolutionary method in forensic genetics, whereby genetic relatives of an unknown target person are detected in direct-to-consumer genomic databases; the family trees of these relatives are then reconstructed to suggest candidates for the target person. Despite recent successes, the full potential of the technology has not yet been systematically evaluated at the scale of an entire country. To estimate the proportion of FIGG cases where a genetic relative is detected in the database (the "match rate"), we used the Israeli population register, covering all past and present citizens. After extensive quality control, the register included 12.4 million individuals, among them 10.4 million alive. We simulated genomic databases by randomly selecting subsets of predefined sizes of the live adult population. With a database covering 1% of the population, we estimate that FIGG would detect at least one relative of fifth degree (e.g., a second cousin) or closer for about 25% of the population, and at least two relatives for 9% of the population. A database covering 5% of the population would find at least one relative of third degree (e.g., a first cousin) or closer for half the population. More distant relatives are rarely identified in the register, likely due to its limited time depth. Our results provide the first country-wide direct estimates for the utility of FIGG in generating investigative leads.

Abstract

How did Homo sapiens thrive in extreme environments during their dispersal across Eurasia? Unraveling adaptations that enabled human survival during the Last Glacial Maximum (LGM) remains critical. Here, we analyze 42 genomes from Holocene hunter-gatherers (Jomon) in the Japanese archipelago, revealing their deep ancestry from an isolated Upper Paleolithic (UP) East Eurasian lineage. We detect gene flow from northern UP Siberians into Jomon, reconciling long-standing debates between bioanthropology and archaeology regarding East Asian peopling. We find no Jomon-specific Denisovan ancestry, suggesting shared introgression before their LGM divergence from mainlanders. Furthermore, we find evidence consistent with cold adaptation in Jomon UP ancestry, highlighting diverse physiological pathways. Our study provides one of the first paleogenomic frameworks for investigating ancient adaptations in UP East Eurasians, revealing an evolutionary legacy from a colder past in present-day humans.

Summary

The genetics of complex traits in Africa has been historically understudied, which can contribute to healthcare inequalities. Here, we present observations of 27 anthropometric, cardiovascular, and blood biomarker measurements across 2,124 individuals from sub-Saharan Africa for whom we also have dense genotype data. First, we identified trait values that differ significantly across populations and subsistence lifestyles (e.g., hemoglobin levels and height). We then identified traits with high degrees of sexual dimorphism (e.g., weight and grip strength). ADMIXTURE analyses revealed substantial population structure in our dataset, and many of the phenotypes studied here are correlated with genetic ancestry components, particularly skin color and body size traits. A variance partitioning approach further revealed traits in which much of the SNP heritability is due to polymorphisms that also contribute to differences between ancestry components. Following genomic imputation, we performed genome-wide association studies (GWASs) for all 27 traits and identified >100 independent autosomal SNPs with genome-wide significant associations for at least one trait (p < 5 × 10^(−8)). Many of these trait-associated variants are rare outside of Africa (minor-allele frequency [MAF] < 1%). We found that 100 kb windows surrounding the top GWAS hits from our African-ancestry cohort were enriched for trait associations in an identically sized European cohort and vice versa. We performed a more detailed analysis of height prediction from genetic data, finding that genome-wide admixture proportions predict height in Africans better than polygenic predictors based on large-scale European height GWASs.

Summary

Early postzygotic mutations (PZMs) that arise after fertilization but prior to primordial germ cell specification may be present in both somatic and germ cells, causing mosaicism in a parent and constitutive inheritance in their offspring. In clinical family-trio whole-genome sequencing (WGS), such variants are systematically missed because their sub-heterozygous variant allele fraction (VAF) prevents heterozygous calling in the parent, while residual parental allele support disqualifies the variant as a candidate germline de novo mutation (DNM) in the child. Here, we developed a bioinformatic approach to ascertain parental PZMs from unfiltered DNM candidates in standard-depth (∼30×) trio WGS and applied it to 12,015 trios from the Genomics England 100,000 Genomes Project. We identified 1,015 high-confidence early autosomal parental PZMs, a large single-source catalog of this mutation class. These exhibited a monomodal VAF distribution centered around 5% in parental blood, consistent with empirically characterized ascertainment boundaries imposed by standard-depth sequencing and germline variant calling. PZMs showed no parental age or sex bias and displayed a mutational spectrum distinct from that of DNMs, with enrichment for C>A and T>A substitutions and depletion of T>C. Mutational signature analysis revealed that both mutation types are shaped by clock-like signatures SBS1 and SBS5 in similar proportions, suggesting that spectral differences reflect shifts within shared mutagenic processes. Exploratory genomic distribution analysis revealed a negative PZM association with GC content, in contrast to the positive association for DNMs. Among these, we found variants in DYNC1H1 and WT1 with potential clinical relevance that were missed by routine diagnostic pipelines.

Highlights

• Specific cognitive abilities (SCA) are 56% heritable, similar to g.
• Some SCA are significantly more heritable than others, 39% to 64%.
• Independent of g (‘SCA.g’), SCA remain substantially heritable (∼50%).
• SCA do not show the dramatic developmental increase in heritability seen for g.
• Genomic research on SCA.g is needed to create profiles of strengths and weaknesses.

Abstract

During the Last Glacial Maximum (LGM) 26-19 thousand years ago (kya), Europe had three principal refugia not covered by ice: the Iberian, Italian, and Balkan peninsulas1,2. While the Iberian and Italian refugia have been studied with ancient DNA3-7, the legacy of the Balkan refugium has remained a mystery due to a lack of genetic data 30-12 kya. We present genome-wide data from nine newly reported individuals: three Epipaleolithic from Romania, one Epipaleolithic from Bosnia and Herzegovina, three Mesolithic from Greece, one Epipaleolithic from Southern Italy, and one Mesolithic from Sardinia. We find that the Epipaleolithic individuals from Romania and the Mesolithic individual from mainland Greece were from a previously unsampled population that was the primary source for later European hunter-gatherers. Westward expansion of Balkan Epipaleolithic people into the Italian Peninsula and mixture with a minority contribution from pre-LGM Italians, pro-duced a population that then spread further west to become the primary ancestry of west-ern European Mesolithic people. Northeastward expansion, bypassing Italy, contributed the European ancestry source of Scandinavian and Eastern European hunter-gatherers. Southeastward expansion to the Aegean led to Anatolian-European mixtures before the spread of farming.

Abstract

Denisovans are an extinct archaic Homo group whose lineage diverged from the Neanderthal lineage approximately 550,000 years ago and were widely distributed across eastern Asia until ~45,000 years ago1-7. Their morphological features are known directly from the existing cranio-dental and phalangeal remains1,2,8-12. However, the body size and postcranial morphology of the Denisovans remain largely unknown. We here report that hominin femoral and tibial fossils recovered from the Penghu Channel, Taiwan, are Denisovans in their proteomic profiles. Morphologically, these specimens are among the largest leg bones known in Pleistocene Homo. They exhibit generally archaic features, but also show some modern human-like morphology, including a strong femoral pilaster. Our findings demonstrate that the Denisovan population at the northern circle had larger body size than earlier Homo erectus as well as Late Pleistocene Homo sapiens in eastern Asia. This challenges the generally held expectation that Pleistocene Homo followed Bergmanns rule that anticipates latitudinal decline of body size, and suggests that the large Denisovan brain resulted from their large body size at least partly. The strong pilaster developed in the Penghu femur suggests some behavioral similarities between the Denisovans and the Upper Palaeolithic modern humans and/or gene flow from the latter to the former.

How prehistoric migrations and dietary shifts shaped genetic diversity is a central question in human history. However, the lack of high-coverage ancient genomes from East Eurasia limits high-resolution reconstruction. This study presented high-coverage genomes from Jomon and Yayoi individuals, revealing contrasting population histories that align with the distinct cultural backgrounds of indigenous lineages and continental ancestry. Notably, the higher AMY1 copy number observed in the Initial Jomon individual suggests that copy number variation at this salivary amylase locus, potentially relevant to starch-rich diets, was already present before rice farming became widely established in the Japanese Archipelago. By providing high-coverage ancient genomic evidence, this study elucidated how the interplay of cultural shifts and migrations formed the basis of modern Japanese populations.

Highlights

•Neanderthals had two amino acid changes in the growth hormone receptor

•One amino acid change drives faster cell growth and stronger STAT5 signaling

•A DNA segment encoding the Neanderthal receptor entered modern humans via admixture

•Carriers have greater muscle mass and some Neanderthal-like craniofacial traits

Summary

Neanderthals had a robust build and distinctive skeletal features. The hypothalamic-pituitary-somatotropic (HPS) axis, with growth hormone (GH) as a central signaling molecule, plays a crucial role in regulating skeletal development. To explore whether Neanderthal-specific genetic variations in the HPS axis contributed to their physical robustness, we examined genes encoding the relevant receptors and hormones. We find that the Neanderthal growth hormone receptor (GHR) carried two amino acid changes and one deletion. When the Neanderthal GHR is expressed in a GH-dependent cell line, the cells proliferate faster than cells expressing the modern human GHR when stimulated by pituitary GH but not by placental GH. We also show that some present-day humans have inherited the gene encoding the Neanderthal GHR. These individuals tend to have more muscle mass and exhibit some craniofacial traits reminiscent of Neanderthals. Thus, aspects of Neanderthal anatomy live on in people today.

Background

Eastern hunter-gatherers (EHG) contributed varying proportions of genetic ancestry to many modern Europeans. However, how this contribution shaped the human leukocyte antigen (HLA) gene diversity remains unexplored. Sakhtysh in western Russia comprises one of the largest EHG-affiliated burial complexes. The site's continuous use offers a rare opportunity to investigate the genetic history, immune-gene diversity, and pathogen exposure within a hunter-gatherer population.

Results

Genome-wide data from 36 individuals (spanning Lyalovo–Volosovo traditions, 6800–4800 cal BP) place the Sakhtysh population within the EHG cluster, with high genetic affinity to contemporaneous groups across northwestern Russia and the eastern Baltic. This genetic composition remained stable for over two millennia and there is no evidence of admixture with neighboring western hunter-gatherer or farmer groups. We report HLA genotypes for 27 Sakhtysh individuals, representing the first true HLA calls from ancient hunter-gatherers. HLA diversity is low in the Sakhtysh population, likely due to their small population size. Specific alleles like B*27:05 are observed at high frequencies (~ 50%), despite being relatively rare in modern populations, suggesting shifts in selective pressures. Pathogen screening identified a restricted spectrum of causal agents including possible zoonoses with Erysipelothrix rhusiopathiae and chronic infections with hepatitis B virus and parvovirus B19.

Conclusions

The Sakhtysh community shows genetic continuity across cultural transitions. This population exhibits limited HLA diversity and unexpectedly high frequency of certain alleles. These patterns were likely influenced by low pathogen diversity and possible adaptation to specific environmental factors.

Abstract

Fibromyalgia is a common and debilitating chronic pain syndrome of poorly understood etiology. Here we conduct a multi-ancestry genome-wide association study meta-analysis across 2,563,755 individuals (54,629 cases and 2,509,126 controls) from 11 cohorts, identifying 26 risk loci for fibromyalgia. The strongest association was with a coding variant in HTT, the causal gene for Huntington’s disease. Gene prioritization implicated the HTT regulator GPR52, as well as diverse genes with neural roles, including DCC, DRD2/NCAM1, MDGA2 and CELF4. Fibromyalgia heritability was exclusively enriched within brain tissues and neural cell types. Fibromyalgia showed strong, positive genetic correlation with a wide range of chronic pain, psychiatric and somatic disorders, including genetic correlations above 0.7 with low back pain, post-traumatic stress disorder and irritable bowel syndrome. Despite large sex differences in fibromyalgia prevalence, the genetic architecture of fibromyalgia was nearly identical between males and females. This study provides robust genetic evidence defining fibromyalgia as a central nervous system disorder, thereby establishing a biological framework for its complex pathophysiology and extensive clinical comorbidities.

Abstract

Modern biobanks are providing numerous high-resolution genomic sequences of diverse populations. In order to account for diverse and admixed populations, new algorithmic tools are needed in order to properly capture the genetic composition of populations. Here, we explore deep learning techniques, namely, variational autoencoders (VAEs), to process genomic data from a population perspective. We show the power of VAEs for a variety of tasks relating to the interpretation, compression, classification, and simulation of genomic data with several worldwide whole genome data sets from both humans and canids, and evaluate the performance of the proposed applications with and without ancestry conditioning. The unsupervised setting of autoencoders allows for the detection and learning of granular population structure and inferring of informative latent factors. The learned latent spaces of VAEs are able to capture and represent differentiated Gaussian-like clusters of samples with similar genetic composition on a fine scale from single nucleotide polymorphisms (SNPs), enabling applications in dimensionality reduction and data simulation. These individual genotype sequences can then be decomposed into latent representations and reconstruction errors (residuals), which provide a sparse representation useful for lossless compression. We show that different populations have differentiated compression ratios and classification accuracies. Additionally, we analyze the entropy of the SNP data, its effect on compression across populations, and its relation to historical migrations, and we show how to introduce autoencoders into existing compression pipelines.

Abstract

Background: Polygenic risk scores (PRS) have proven valuable for disease risk prediction, but their predictive utility often remains limited because human traits result from complex interactions between environmental and genetic factors. Blood lipid levels are heritable and clinically important risk factors for cardiovascular disease, yet it remains unclear whether multi-omics integration can enhance lipid trait prediction beyond PRS alone. Methods: We first constructed single-omics scores, where gene expression, plasma protein, and plasma/serum metabolite levels were genetically predicted and weighted by effect sizes estimated via LASSO regression. Subsequently, we implemented two integration strategies to develop composite multi-omics risk scores (MoRS): step-MoRS, which integrates single-omics scores using stepwise regression, and Lasso-MoRS, which directly models all predicted features across omics layers using LASSO regression. Both approaches were evaluated across European, South Asian, and African ancestries within the UK Biobank. Results: MoRS-based methods consistently demonstrated superior predictive accuracy compared to PRS alone for four lipid traits across diverse populations. Notably, Lasso-MoRS prioritized key biomarkers with predictive utility complementary to genomic data. Conclusions: These findings confirm that integrating multi-omics biomarkers with genomic data significantly enhances lipid trait prediction across diverse ancestries, offering biological insights into the molecular regulation of lipid metabolism.

Summary

Understanding how selection shapes disease risk remains challenging. Variants influencing complex traits, including common diseases, can also impact fitness and thus be constrained by purifying selection. Consequently, genetic variance underlying disease susceptibility may be attributed to low-frequency, population-specific variants. We analyzed 509,817 genome-wide variants from 72,635 Han Taiwanese individuals to identify loci showing age-dependent allele frequency shifts that signal ongoing selection. After adjusting for potential age-related population structure, we detected 168 variants deviating from neutrality, with most showing declining frequencies in younger generations, consistent with purifying selection on deleterious alleles influencing disease risk. These variants were enriched for rare alleles (≤0.1%) and disease-associated variants. At BRCA1, we identified 16 rare pathogenic variants in strong linkage disequilibrium undergoing purifying selection that coexist with a positively selected haplotype, revealing temporally fluctuating selection; comparable patterns at BRCA2 and MLH1 suggest recurrent selective trade-offs in DNA repair genes. Phenome-wide association analysis across 30 hematologic and cardiometabolic traits linked a subset of candidates to increased erythrocyte volume and reduced hemoglobin concentration, suggesting subclinical physiological effects. These results demonstrate ongoing natural selection on disease-relevant variation, particularly affecting hematologic traits in the Han Taiwanese population, and highlight opportunities to refine precision-medicine risk models.

Abstract

A pangenome reference overcomes the inherent limitation of any individual reference genome by integrating the variation present in a population. We present the Human Pangenome Reference Consortium's (HPRC) Release 2 (HPRC2), an openly available, second phase pangenome that is an approximately fivefold expansion in genome number over HPRC Release 1 (HPRC1) and measurable improvement in genome completeness, contiguity, and accuracy. Selecting samples with a principled algorithm prioritising common variant coverage, HPRC2 contributes 460 haplotypes that together capture over 99% of common variation observed in the All of Us Research Program v8 cohort. Combining high-coverage long and ultra-long reads with modern assemblers and polishers, we produce thousands of telomere-to-telomere (T2T) chromosomes, and relative to HPRC1 halve the number of structurally unreliable regions as well as individual base errors per haplotype. We complement the assemblies with whole genome multiple alignments and gene annotations, and derive formal pangenome coordinate systems for addressing off-reference variation, demonstrating that individual human genomes contain more than one hundred thousand variants not succinctly described with respect to existing reference genomes. We also present the first matched long-read backed pantranscriptome and panepigenome at this scale, provide continuous local-ancestry estimates spanning every genome, and outline a host of new tools and applications that leverage the pangenome resource for improved genomics analysis.

Abstract

The nomadic cultures of the Iron Age played an important role in shaping the genetic and cultural landscape of Eurasian populations. Yet despite its key geographical location, the Central Eurasian region remains underrepresented in ancient DNA studies of humans. We address this gap through genomic analysis of 12 individuals from the Boz-Barmak burial site in Kyrgyzstan associated with Saka pastoralists (4th−2nd centuries BCE), 9 of which yielded low-coverage genomes (on average 0.7-fold coverage). Genetic clustering analysis placed these individuals within the genetic variation of ancient and modern Central Eurasian and Siberian populations. We found no evidence of first-degree relatives in a kinship analysis, however a network of second- and third-degree relationships seems to be present. Notably, all male individuals share the same Y-chromosomal haplotype, common in present-day Kyrgyz groups, while mitochondrial DNA showed comparably high diversity, with distinct haplogroups observed across the analysed individuals. These findings are in line with archaeological and ethnographic evidence of patrilocality in Early Iron Age Saka, where male lineages remained stable across generations, while female mobility contributed to genetic diversity. Our study complements our understanding of the interplay between kinship, social organisation and population history in nomadic cultures.

Borderline personality disorder (BPD) is a severe mental health condition influenced by environmental risk factors (for example, interpersonal trauma) and genetic factors. We conducted the largest genome-wide association study (GWAS) meta-analysis of BPD so far, with a discovery sample of 12,339 cases and 1,041,717 controls, and a replication study of 685 cases and 107,750 controls (all participants of European ancestry). We identified 11 independent associated genomic loci and 9 risk genes in gene-based analyses. We observed a single-nucleotide polymorphism heritability of 17.3% and derived polygenic scores (PGS) that predicted 4.6% of the phenotypic variance in BPD on the liability scale. BPD showed the strongest positive genetic correlations with GWAS of post-traumatic stress disorder, depression, attention deficit hyperactivity disorder, antisocial behavior, and measures of suicide and self-harm. Phenome-wide analyses in Vanderbilt University Medical Center Biobank and UK Biobank using BPD-PGS confirmed these associations and also identified associations with other medical conditions, including obstructive pulmonary disease and diabetes. These analyses highlight BPD as a polygenic disorder, with the genetic risk showing substantial overlap with psychiatric and physical health conditions.