Annals of Human Genetics最新文献

{"title":"MYLK c.4079G>A, p.(Gly1360Asp) Variant Associated With Hereditary Thoracic Aortic Diseases and Early Onset Aortic Dissection.","authors":"Minja Virtanen, Sini Keskinen, Rikhard Björn, Minna Paavola, Pia Pohjola, Marja Hietala, Maria K Haanpää, Markus Malmberg, Elisa Rahikkala","doi":"10.1111/ahg.70064","DOIUrl":"https://doi.org/10.1111/ahg.70064","url":null,"abstract":"<p><strong>Aims: </strong>Thoracic aortic aneurysms and dissections are major causes of sudden cardiovascular death. We aimed to evaluate the clinical significance of the MYLK c.4079G>A, p.(Gly1360Asp) variant in Finnish families with heritable thoracic aortic disease (HTAD) and to assess evidence for a potential founder effect.</p><p><strong>Methods: </strong>We evaluated the clinical significance and potential founder effect of the missense variant MYLK c.4079G>A, p.(Gly1360Asp) in Finnish families. Eight individuals from four unrelated Finnish families carrying the MYLK c.4079G>A heterozygous variant were recruited. Clinical histories, imaging data, and pedigrees were reviewed. Genetic testing included exome‑based gene panel sequencing or targeted familial variant testing. Variant classification followed the American College of Medical Genetics and Genomics 2015 guidelines.</p><p><strong>Results: </strong>Thoracic aortic dilatation or aneurysm occurred in 6/8 carriers (75%), with a mean age at diagnosis of 45 years (range 34-67). Ascending aortic diameters ranged from 26-59 mm, most often measured at the aortic root. Aortic dissection occurred in 4/8 (50%) at a mean age of 46 years (range 34-68), including three early‑adult events. Extrathoracic arterial involvement (carotid) was observed in one variant‑positive individual.</p><p><strong>Conclusion: </strong>The MYLK c.4079G>A, p.(Gly1360Asp) variant was present in six affected individuals from four unrelated families and is enriched in the Finnish population, supporting a founder effect. The MYLK c.4079G>A, p.(Gly1360Asp) variant is associated with early‑adult‑onset, high‑penetrance thoracic aortic disease and substantial dissection risk, underscoring the need for vigilant surveillance and early intervention in affected individuals and at‑risk relatives.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence for Reduced Somatic T-Cell Receptor Sequence Diversity Profiles Among Midwestern Amish in an Aging Cohort Study.","authors":"Lauren A Cruz, Shiying Liu, Kristy L Miskimen, Jessica N Cooke Bailey, Tyler Kinzy, Yeunjoo E Song, Renee A Laux, Penelope Miron, Paula K Ogrocki, Alan J Lerner, Audrey Lynn, Sarada L Fuzzell, Sherri D Hochstetler, Ioanna Konidari, Jacob L McCauley, William K Scott, Margaret A Pericak-Vance, Jonathan L Haines, Dana C Crawford","doi":"10.1111/ahg.70063","DOIUrl":"https://doi.org/10.1111/ahg.70063","url":null,"abstract":"<p><strong>Background: </strong>The causes of late onset Alzheimer disease (LOAD) are not known but several recent lines of evidence implicate the adaptive immune system.</p><p><strong>Objective: </strong>To characterize the adaptive immune system among Midwestern Amish participating in longitudinal studies of aging.</p><p><strong>Methods: </strong>We immunosequenced the T-cell receptor (TCR) beta chain from genomic DNA of 72 participants, including those with clinically diagnosed LOAD (n = 6), mild cognitive impairment (MCI; n = 16), cognitive impairment but not AD (n = 3), and 35 cognitively unaffected. For a subset of participants, LOAD pathogenesis plasma biomarkers were available.</p><p><strong>Results: </strong>TCR sequence diversity measured as Simpson's clonality was lower among LOAD+MCI compared with non-LOAD, but these differences were not independent of age. Relatively few clonotypes (exact nucleotide sequences) were shared across participants; of those few shared include the Epstein Barr virus associated clonotype. HLA-A*03:01 and several HLA-DRB1 alleles were under-represented among LOAD+MCI participants compared with cognitively unaffected participants, but these associations were no longer significant in adjusted analyses. Among LOAD+MCI participants, increased p-tau181 was nominally associated with decreased TCR sequence diversity, and the nominal association was independent of age; however, this association did not remain statistically significant after strict correction for multiple testing and the limited sample size precluded formal tests of heterogeneity.</p><p><strong>Results: </strong>In this limited Midwestern Amish sample, the preliminary TCR diversity trends are consistent with the involvement of the adaptive immune system in LOAD.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149215036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population-Level Nucleotide Diversity and Genetic Differentiation at SOD1 Across Global Human Populations","authors":"Sergio V. Flores,&nbsp;Patricia Lillo,&nbsp;Jorge Briceño-Moya","doi":"10.1111/ahg.70052","DOIUrl":"10.1111/ahg.70052","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The <i>SOD1</i> gene encodes superoxide dismutase 1, an antioxidant enzyme in which pathogenic variants cause a subset of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although the clinical and molecular consequences of <i>SOD1</i> variants are well established, its locus-wide population genetic architecture has not been systematically characterized across global populations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To characterize patterns of genetic diversity, population differentiation, and evolutionary constraint across the <i>SOD1</i> locus in worldwide human populations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed genomic variation spanning the <i>SOD1</i> region in the five continental populations of the 1000 Genomes Project. Nucleotide diversity (π), fixation index (FST), and allele frequency distributions were estimated using sliding-window analyses. Bootstrap resampling was used to compare diversity within and outside the coding region. Recent positive selection was assessed using XP-nSL, and codon-based evolutionary analyses were performed using primate <i>SOD1</i> orthologs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The coding region consistently exhibited a twofold to threefold reduction in nucleotide diversity relative to adjacent genomic sequences across all populations. Bootstrap analyses confirmed significantly lower diversity within the locus than in flanking regions (<i>p</i> &lt; 0.05 in all populations). Population differentiation was low (mean FST ≈ 0.03) and showed no pronounced peaks within the coding interval, whereas allele frequency distributions were broadly similar across continental populations. XP-nSL analyses detected no evidence of population-specific recent selective sweeps. Codon-based analyses identified only 31 variable codons among 155 analyzed positions, six codons under negative selection, and no evidence of positive selection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The <i>SOD1</i> locus exhibits reduced standing genetic variation, limited continental differentiation, and strong evolutionary conservation, consistent with sustained functional constraint. These findings provide a comprehensive population genetic framework for interpreting genetic variation at this medically important locus.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"90 6","pages":"340-345"},"PeriodicalIF":1.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148757507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exome Sequencing Identifies Novel Variants Causing Hearing Loss in Three Consanguineous Pakistani Families: Insights From Genomics and Bioinformatics Analyses","authors":"Zafar Ali,&nbsp;Najeeb Ullah,&nbsp;Muneeba Bibi,&nbsp;Sania Fawad,&nbsp;Sana Khan,&nbsp;Mansoor Ali,&nbsp;Irum Hassan,&nbsp;Sana Fazal,&nbsp;Fazal Akbar,&nbsp;Shahid Baig,&nbsp;Niklas Dahl","doi":"10.1111/ahg.70061","DOIUrl":"10.1111/ahg.70061","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Hearing impairment is a genetically heterogeneous disorder and represents a significant health concern, particularly in consanguineous populations where autosomal recessive forms are more prevalent. Pakistani families provide an important population for investigating the genetic basis of hereditary hearing impairment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The current study was aimed to elucidate the genetic basis of hearing impairment in consanguineous Pakistani families.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Material and Methods</h3>\u0000 \u0000 <p>Three consanguineous Pakistani families comprising 11 affected individuals presenting bilateral profound hearing loss were investigated using Exome Sequencing (ES). Sanger sequencing was used for segregation analysis of candidate variant(s) in each pedigree. Structural modeling of both wild-type and mutant proteins were performed using bioinformatic tools to assess the functional impact of candidate variants.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>ES data analysis revealed homozygous missense variants in <i>MSRB3</i> (c.244T&gt;G; p.Cys82Gly), <i>ESRP1</i> (c.353T&gt;C; p.Leu118Pro) and <i>TMC1</i> (c.1749C&gt;G; p.Asn583Lys) in family 1, 2, and 3 respectively. These variants are predicted to be “deleterious” by multiple bioinformatic tools, affecting highly conserved residues of candidate protein, and are absent in homozygous form in public databases. Sanger sequencing validated the co-segregation of the candidate variants within their respective families. Structural modeling of the wild-type and mutant proteins predicted that the candidate variants lead to structural alterations that strengthens the evidence supporting their pathogenicity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study expands the mutational spectrum of <i>MSRB3</i>, <i>ESRP1</i> and <i>TMC1</i> genes associated with hearing loss. Furthermore, carrier screening and genetic counselling can be developed for affected families based on the findings obtained from the current study. The data obtained may also enhance our understanding of the pathophysiology of hearing loss ultimately guiding us in the development of potential therapeutics.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"90 6","pages":"357-365"},"PeriodicalIF":1.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trans-Ancestry Psychiatric Genomics in Admixed Populations: Advances, Challenges, and Future Directions","authors":"Sergio Flores Carrasco,&nbsp;Ángel Roco-Videla,&nbsp;Jorge Briceño-Moya,&nbsp;Román Montaña","doi":"10.1111/ahg.70048","DOIUrl":"10.1111/ahg.70048","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Early genome-wide association studies (GWAS) of psychiatric disorders were conducted predominantly in European populations, limiting the understanding of genetic architecture across ancestries.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>To summarize current evidence on shared and ancestry-specific genetic architecture in major psychiatric disorders.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We reviewed findings from multi-ancestry GWAS, trans-ancestral meta-analyses, fine-mapping, polygenic risk score, and local ancestry studies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Common-variant liability is largely shared across ancestries, with high genetic correlations and overlapping biological pathways. However, locus transferability, fine-mapping resolution, and polygenic score performance differ because of variation in linkage disequilibrium, allele frequencies, environmental exposures, and local ancestry. Rare and structural variants further contribute to ancestry-specific risk.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Psychiatric disorders are characterized by a shared polygenic substrate embedded within ancestry-specific genomic architecture and context-dependent penetrance. Future studies should integrate diverse and admixed populations to improve biological discovery and equitable clinical translation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"90 6","pages":"332-339"},"PeriodicalIF":1.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.70048","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148590206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Evidence of a Protective Effect of Metformin on Abdominal Aortic Aneurysm Risk: Insights from an Observational Study and Mendelian Randomisation Analysis Using Putative Metformin Targets”","authors":"","doi":"10.1111/ahg.70059","DOIUrl":"10.1111/ahg.70059","url":null,"abstract":"<p>Saxby, K. L., S. Stoma, F. Dudbridge, N. J. Samani, M. J. Bown, and C. P. Nelson. 2026. “Evidence of a Protective Effect of Metformin on Abdominal Aortic Aneurysm Risk: Insights From an Observational Study and Mendelian Randomisation Analysis Using Putative Metformin Targets.” <i>Annals of Human Genetics 90</i>, no. 5: 294–302. https://doi.org/10.1111/ahg.70049</p><p>In the funding acknowledgement section, the grant reference for the British Heart Foundation Leicester Centre of Research Excellence was stated as being [RE/34/130031]. This grant reference number is incorrect and should be RE/24/130031.</p><p>We apologize for this error.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"90 6","pages":""},"PeriodicalIF":1.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.70059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Diversity and Historical Divergence of Malays and Indigenous Populations in Peninsular Malaysia and Northern Borneo","authors":"Woei-Yuh Saw,&nbsp;Chee Wei Yew,&nbsp;Thuhairah Abdul Rahman,&nbsp;Mohammad Zahirul Hoque,&nbsp;Shuhua Xu,&nbsp;Chiea-Chuen Khor,&nbsp;Vijay Kumar Subbiah,&nbsp;Yik-Ying Teo,&nbsp;Boon-Peng Hoh","doi":"10.1111/ahg.70036","DOIUrl":"10.1111/ahg.70036","url":null,"abstract":"<div>\u0000 \u0000 <p>Previous studies have highlighted significant genetic structure among Southeast Asian populations, with Northern Borneo natives closely related to Austronesians from Taiwan and the Philippines, and Peninsular Malaysia indigenous populations potentially linked to the indigenous Andamanese. In this study, we analyzed 96 genomes from indigenous populations in Peninsular Malaysia, genotyped with approximately 2 million genome-wide autosomal SNPs, alongside datasets from Singapore cosmopolitan Malays and five native populations from Sabah, Northern Borneo. Our findings reveal distinct genetic structures between indigenous populations and Malays, despite their shared habitat. The Malays exhibit substantial admixture with East Asian, Austronesian, and indigenous Peninsular Malaysian ancestral components. Indigenous populations showed lower within-population diversity and longer linkage disequilibrium compared to benchmark populations. Estimated divergence times suggest that the Semang represent an earlier branching population (∼10,000 years ago), followed by Northern Borneo natives (∼7,600–6,H800 years ago), with Malays diverging more recently. These results support a scenario of successive migration waves into Southeast Asia, providing insights into the genetic history and population structure of the region.</p>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"90 6","pages":"317-331"},"PeriodicalIF":1.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ancestry-Stratified Variant Classification in Monogenic Diabetes Genes: Annotation Coverage and Differential Curation Burden","authors":"Paulo Dario","doi":"10.1111/ahg.70054","DOIUrl":"10.1111/ahg.70054","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Variant databases ClinVar and gnomAD underpin clinical variant interpretation, but their composition is skewed toward European ancestry. Whether this produces systematic disadvantages for non-European patients with monogenic diabetes has not been examined at the database level with mutually exclusive ancestry groups.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To quantify ClinVar annotation coverage and ancestry-stratified classification outcomes across monogenic diabetes genes, using mutually exclusive population-private variant groups.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>gnomAD v4.0 (genomes and exomes; 807,162 individuals) was cross-referenced with the ClinVar GRCh38 record (accessed June 29, 2026) for 16 monogenic diabetes (maturity-onset diabetes of the young [MODY]) genes, and variants were classified as population-private to European or non-European ancestry from ancestry-specific allele counts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Across 54,865 gnomAD variants, 86.7% carried no ClinVar classification. The annotation gap was near-universal rather than ancestry-specific (unannotated fraction 89.4% European-private, 87.5% non-European-private). Among classified population-private variants, however, the pathogenic or likely pathogenic rate was 19.8% for European-private but only 8.6% for non-European-private variants (Fisher exact OR 2.6, 95% CI 2.1–3.3, <i>p</i> = 1 × 10⁻¹⁸), with a higher uncertain-significance rate in non-European-private variants (52.1% vs. 45.8%).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The dominant problem is therefore an annotation deficit affecting all ancestries; the ancestry inequity the data support is one of actionability, not of raw uncertain-significance rates. Closing it requires ClinVar submissions and population-specific sequencing from underrepresented populations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"90 6","pages":"346-355"},"PeriodicalIF":1.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Report on the 29th Human Genome Meeting: 'Bringing Our Genomes to Medicine'.","authors":"Laith Gergi, Rosemary Ekong","doi":"10.1111/ahg.70060","DOIUrl":"https://doi.org/10.1111/ahg.70060","url":null,"abstract":"","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":""},"PeriodicalIF":1.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"What Uniparental Lineages Tell Us About the Prehistoric Human Colonization of the Americas.","authors":"Vicente M Cabrera","doi":"10.1111/ahg.70053","DOIUrl":"https://doi.org/10.1111/ahg.70053","url":null,"abstract":"<p><strong>Objectives: </strong>From the perspective of uniparental markers, the view of the human prehistoric settlement of America is that it resulted from a single main migration after the Last Glacial Maximum, following a long or short period of genetic isolation in Beringia. Ancient DNA and whole genome analyses have confirmed this view. My objective here is to demonstrate that humans entered America before the LGM and that the documented post-LGM expansions began in South instead of North America.</p><p><strong>Methods: </strong>In this work, I have reanalyzed all publicly available mitochondrial DNA and Y-chromosome haplogroups in the American population using simple phylogenetic and phylogeographic methodologies.</p><p><strong>Results: </strong>The arrival of the American settlers occurred more than 30,000 years ago, preceding the LGM. As genomic studies have uncovered, at least two Asian populations contributed to the ancestry of the immigrant population. Low population density and climatic deterioration led to a long period of demographic eclipse, during which small bands of hunter-gatherers made long journeys in search of favorable niches. After the LGM, the climate improved, and demographic expansions occurred in multiple independent centers. The founding and expansion ages of the uniparental haplogroups indicate that these centers were in South America, particularly the Colombian isthmus, the Andean region, the Southern Cone, and the Amazon. Subsequent dispersals occurred in North America, one involving mitochondrial haplogroups A2, C1, and D1, but not B2, and another, of lesser magnitude, represented by the expansion of haplogroups C4c and X2a.</p><p><strong>Conclusion: </strong>This work offers a previously unexplored model for the colonization of the Americas.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":"e70053"},"PeriodicalIF":1.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148954786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}