Continental-scale genomic analysis suggests shared post-admixture adaptation in the Americas

We thank the people working at the High Performance Computing Center of the University of Tartu for the help and support provided. We thank Marco Rosario Capodiferro for useful discussions. This work was supported by the European Union through the European Regional Development Fund (Project No. 20142020.4.01.16-0030 to LO, MMe, FM; Project No. 2014-2020.4.01.160271 to RF; Project No. 2014-2020.4.01.16-0125 to RF; Project No. 2014-2020.4.01.16-0024 to DM, LP). This work was supported by the Estonian Research Council grant PUT (PRG243) (to RF, MMe, LP). This work was supported by institutional research funding IUT (IUT24-1) of the EstonianMinistry of Education and Research (to TK). This research was supported by the European Union through Horizon 2020 grant no. 810645 (to MMe). This research was supported by the European Union through the Horizon 2020 research and innovation programme under grant no 810645 and through the European Regional Development Fund project no. MOBEC008 to MMo.American populations are one of the most interesting examples of recently admixed groups, where ancestral components from three major continental human groups (Africans, Eurasians and Native Americans) have admixed within the last 15 generations. Recently, several genetic surveys focusing on thousands of individuals shed light on the geography, chronology and relevance of these events. However, even though gene f low could drive adaptive evolution, it is unclear whether and how natural selection acted on the resulting genetic variation in the Americas. In this study, we analysed the patterns of local ancestry of genomic fragments in genome-wide data for ∼6000 admixed individuals from 10 American countries. In doing so, we identified regions characterized by a divergent ancestry profile (DAP), in which a significant over or under ancestral representation is evident. Our results highlighted a series of genomic regions with DAPs associated with immune system response and relevant medical traits, with the longest DAP region encompassing the human leukocyte antigen locus. Furthermore, we found that DAP regions are enriched in genes linked to cancer-related traits and autoimmune diseases. Then, analysing the biological impact of these regions, we showed that natural selection could have acted preferentially towards variants located in coding and non-coding transcripts and characterized by a high deleteriousness score. Taken together, our analyses suggest that shared patterns of post admixture adaptation occurred at a continental scale in the Americas, affecting more often functional and impactful genomic variants.European Commission 2014-2020.4.01.16-0030 2014-2020.4.01.16-0271 2014-2020.4.01.16-0125 2014-2020.4.01.16-0024 MOBEC008Estonian Research Council grant PUT PRG243institutional research funding IUT of the Estonian Ministry of Education and Research IUT24-1European Union through Horizon 2020 grant 81064

Evaluating the Impact of Sex-Biased Genetic Admixture in the Americas through the Analysis of Haplotype Data

This work was supported by the European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.16-0030 to LO, LM, MM, FM; Project No. 2014-2020.4.01.16-0271 to RF; Project No. 2014-2020.4.01.16-0125 to RF; Project No. 2014-2020.4.01.16-0024 to LM, DM, LP; Project No. 2014-2020.4.01.15-0012 to MM; Project no. MOBEC008 to MM). This work was supported by the Estonian Research Council grant PUT (PRG243) to RF and MM and PUT (PRG1027) to KT. This research was supported by the European Union through Horizon 2020 research and innovation programme under grant no 810645 to MM and no 824110 to KT. AA and MRC received support from the Italian Ministry of Education, University and Research (MIUR) for Progetti PRIN2017 20174BTC4R and the Dipartimenti di Eccellenza Program (2018-2022).A general imbalance in the proportion of disembarked males and females in the Americas has been documented during the Trans-Atlantic Slave Trade and the Colonial Era and, although less prominent, more recently. This imbalance may have left a signature on the genomes of modern-day populations characterised by high levels of admixture. The analysis of the uniparental systems and the evaluation of continental proportion ratio of autosomal and X chromosomes revealed a general sex imbalance towards males for European and females for African and Indigenous American ancestries. However, the consistency and degree of this imbalance are variable, suggesting that other factors, such as cultural and social practices, may have played a role in shaping it. Moreover, very few investigations have evaluated the sex imbalance using haplotype data, containing more critical information than genotypes. Here, we analysed genome-wide data for more than 5000 admixed American individuals to assess the presence, direction and magnitude of sex-biased admixture in the Americas. For this purpose, we applied two haplotype-based approaches, ELAI and NNLS, and we compared them with a genotype-based method, ADMIXTURE. In doing so, besides a general agreement between methods, we unravelled that the post-colonial admixture dynamics show higher complexity than previously described.European Commission 2014-2020.4.01.16-0030 2014-2020.4.01.16-0271 2014-2020.4.01.16-0125 2014-2020.4.01.16-0024 2014-2020.4.01.15-0012MOBEC008Estonian Research Council grant PUT PRG243 PRG1027European Commission 810645 824110Ministry of Education, Universities and Research (MIUR) PRIN2017 20174BTC4

Variation in the ICAM1-ICAM4-ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries

Objective: Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin ?M(complement component 3 receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM. Methods: The authors examined several markers in the ICAM1-ICAM4-ICAM5 locus on chromosome 19p13 and the single ITGAM polymorphism (rs1143679) using a large-scale case-control study of 17 481 unrelated participants from four ancestry populations. The singlemarker association and gene-gene interaction were analysed for each ancestry, and a meta-analysis across the four ancestries was performed. Results: The A-allele of ICAM1-ICAM4-ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAM rs1143679 showed the strongest association with increased SLE susceptibility in each of the ancestry populations and the trans-ancestry meta-analysis (ORmeta=1.16, 95% CI 1.11 to 1.22; p=4.88 × 10-10 and ORmeta=1.67, 95% CI 1.55 to 1.79; p=3.32 × 10-46, respectively). The effect of the ICAM single-nucleotide polymorphisms (SNPs) was independent of the effect of the ITGAM SNP rs1143679, and carriers of both ICAM rs3093030-AA and ITGAM rs1143679-AA had an OR of 4.08 compared with those with no risk allele in either SNP (95% CI 2.09 to 7.98; p=3.91 × 10-5). Conclusion: These findings are the first to suggest that an ICAM-integrin-mediated pathway contributes to susceptibility to SLE

Reduced Cancer Incidence in Huntington's Disease: Analysis in the Registry Study

Background: People with Huntington's disease (HD) have been observed to have lower rates of cancers. Objective: To investigate the relationship between age of onset of HD, CAG repeat length, and cancer diagnosis. Methods: Data were obtained from the European Huntington's disease network REGISTRY study for 6540 subjects. Population cancer incidence was ascertained from the GLOBOCAN database to obtain standardised incidence ratios of cancers in the REGISTRY subjects. Results: 173/6528 HD REGISTRY subjects had had a cancer diagnosis. The age-standardised incidence rate of all cancers in the REGISTRY HD population was 0.26 (CI 0.22-0.30). Individual cancers showed a lower age-standardised incidence rate compared with the control population with prostate and colorectal cancers showing the lowest rates. There was no effect of CAG length on the likelihood of cancer, but a cancer diagnosis within the last year was associated with a greatly increased rate of HD onset (Hazard Ratio 18.94, p < 0.001). Conclusions: Cancer is less common than expected in the HD population, confirming previous reports. However, this does not appear to be related to CAG length in HTT. A recent diagnosis of cancer increases the risk of HD onset at any age, likely due to increased investigation following a cancer diagnosis