American journal of human genetics最新文献

{"title":"Monoallelic pathogenic variants in LEPR do not cause obesity.","authors":"Jérôme Delplanque, Lauriane Le Collen, Hélène Loiselle, Audrey Leloire, Bénédicte Toussaint, Emmanuel Vaillant, Guillaume Charpentier, Sylvia Franc, Beverley Balkau, Michel Marre, Emma Henriques, Emmanuel Buse Falay, Mehdi Derhourhi, Philippe Froguel, Amélie Bonnefond","doi":"10.1016/j.ajhg.2024.10.014","DOIUrl":"https://doi.org/10.1016/j.ajhg.2024.10.014","url":null,"abstract":"<p><p>Individuals with obesity caused by biallelic pathogenic LEPR (leptin receptor) variants can benefit from setmelanotide, the novel MC4R agonist. An ongoing phase 3 clinical trial (NCT05093634) includes individuals with obesity who carry a heterozygous LEPR variant, although the obesogenic impact of these variants remains incompletely evaluated. The aim of this study was to functionally assess heterozygous variants in LEPR and to evaluate their effect on obesity. We sequenced LEPR in ∼10,000 participants from the French RaDiO study. We found 86 rare heterozygous variants. Each identified variant was then investigated in vitro using luciferase and western blot assays. Using the criteria of the American College of Medical Genetics and Genomics (ACMG), including the strong criterion related to functional assays, we found 12 pathogenic LEPR variants. Most heterozygotes did not present with obesity, and we found no association between these pathogenic variants and body mass index (BMI). This lack of association between pathogenic LEPR variants and obesity risk or BMI was confirmed using exome data from 200,000 individuals in the UK Biobank. In the literature, among 55 reported heterozygotes for of a rare pathogenic LEPR variant, only 27% had obesity. In conclusion, monoallelic pathogenic LEPR variants were functionally tested, and they do not elevate the risk of obesity or BMI levels. This raises questions about the use of setmelanotide, a costly drug with potential side effects, based solely on the presence of a heterozygous LEPR variant.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Profiling genetically driven alternative splicing across the Indonesian archipelago.","authors":"Neke Ibeh, Pradiptajati Kusuma, Chelzie Crenna Darusallam, Safarina G Malik, Herawati Sudoyo, Davis J McCarthy, Irene Gallego Romero","doi":"10.1016/j.ajhg.2024.09.004","DOIUrl":"10.1016/j.ajhg.2024.09.004","url":null,"abstract":"<p><p>One of the regulatory mechanisms influencing the functional capacity of genes is alternative splicing (AS). Previous studies exploring the splicing landscape of human tissues have shown that AS has contributed to human biology, especially in disease progression and the immune response. Nonetheless, this phenomenon remains poorly characterized across human populations, and it is unclear how genetic and environmental variation contribute to AS. Here, we examine a set of 115 Indonesian samples from three traditional island populations spanning the genetic ancestry cline that characterizes Island Southeast Asia. We conduct a global AS analysis between islands to ascertain the degree of functionally significant AS events and their consequences. Using an event-based statistical model, we detected over 1,500 significant differential AS events across all comparisons. Additionally, we identify over 6,000 genetic variants associated with changes in splicing (splicing quantitative trait loci [sQTLs]), some of which are driven by Papuan-like genetic ancestry, and only show partial overlap with other publicly available sQTL datasets derived from other populations. Computational predictions of RNA binding activity reveal that a fraction of these sQTLs directly modulate the binding propensity of proteins involved in the splicing regulation of immune genes. Overall, these results contribute toward elucidating the role of genetic variation in shaping gene regulation in one of the most diverse regions in the world.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2458-2477"},"PeriodicalIF":5.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inverse relationship between polygenic risk burden and age of onset of autoimmune vitiligo.","authors":"Genevieve H L Roberts, Pamela R Fain, Stephanie A Santorico, Richard A Spritz","doi":"10.1016/j.ajhg.2024.09.007","DOIUrl":"10.1016/j.ajhg.2024.09.007","url":null,"abstract":"<p><p>Vitiligo is a common autoimmune disease characterized by patches of depigmented skin and overlying hair due to destruction of melanocytes in the involved regions. We investigated the relationship between vitiligo risk and vitiligo age of onset (AOO) using a vitiligo polygenic risk score that incorporated the most significant SNPs from genome-wide association studies. We find that vitiligo genetic risk and AOO are strongly inversely correlated; subjects with higher common-variant polygenic risk tend to develop vitiligo at an earlier age. Nevertheless, the correlation is not simple. In individuals who carry a single high-risk major histocompatibility complex class II haplotype, the effect of additional polygenic risk on vitiligo AOO is reduced. Particularly among those with early-AOO vitiligo (onset ≤12 years of age), genetic risk can reflect contributions from high common-variant burden but also rare variants of high effect and sometimes both. While the heritability of vitiligo is relatively high, and we here show that genetic risk factors predict vitiligo AOO, vitiligo is never congenital, and thus environmental triggers also play an important role in disease onset.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2561-2565"},"PeriodicalIF":5.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disentangling mechanisms behind the pleiotropic effects of proximal 16p11.2 BP4-5 CNVs.","authors":"Chiara Auwerx, Samuel Moix, Zoltán Kutalik, Alexandre Reymond","doi":"10.1016/j.ajhg.2024.08.014","DOIUrl":"10.1016/j.ajhg.2024.08.014","url":null,"abstract":"<p><p>Whereas 16p11.2 BP4-5 copy-number variants (CNVs) represent one of the most pleiotropic etiologies of genomic syndromes in both clinical and population cohorts, the mechanisms leading to such pleiotropy remain understudied. Identifying 73 deletion and 89 duplication carrier individuals among unrelated White British UK Biobank participants, we performed a phenome-wide association study (PheWAS) between the region's copy number and 117 complex traits and diseases, mimicking four dosage models. Forty-six phenotypes (39%) were affected by 16p11.2 BP4-5 CNVs, with the deletion-only, mirror, U-shape, and duplication-only models being the best fit for 30, 10, 4, and 2 phenotypes, respectively, aligning with the stronger deleteriousness of the deletion. Upon individually adjusting CNV effects for either body mass index (BMI), height, or educational attainment (EA), we found that sixteen testable deletion-driven associations-primarily with cardiovascular and metabolic traits-were BMI dependent, with EA playing a more subtle role and no association depending on height. Bidirectional Mendelian randomization supported that 13 out of these 16 associations were secondary consequences of the CNV's impact on BMI. For the 23 traits that remained significantly associated upon individual adjustment for mediators, matched-control analyses found that 10 phenotypes, including musculoskeletal traits, liver enzymes, fluid intelligence, platelet count, and pneumonia and acute kidney injury risk, remained associated under strict Bonferroni correction, with 10 additional nominally significant associations. These results paint a complex picture of 16p11.2 BP4-5's pleiotropic pattern that involves direct effects on multiple physiological systems and indirect co-morbidities consequential to the CNV's impact on BMI and EA, acting through trait-specific dosage mechanisms.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2347-2361"},"PeriodicalIF":5.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MARK2 variants cause autism spectrum disorder via the downregulation of WNT/β-catenin signaling pathway.","authors":"Maolei Gong, Jiayi Li, Zailong Qin, Matheus Vernet Machado Bressan Wilke, Yijun Liu, Qian Li, Haoran Liu, Chen Liang, Joel A Morales-Rosado, Ana S A Cohen, Susan S Hughes, Bonnie R Sullivan, Valerie Waddell, Marie-José H van den Boogaard, Richard H van Jaarsveld, Ellen van Binsbergen, Koen L van Gassen, Tianyun Wang, Susan M Hiatt, Michelle D Amaral, Whitley V Kelley, Jianbo Zhao, Weixing Feng, Changhong Ren, Yazhen Yu, Nicole J Boczek, Matthew J Ferber, Carrie Lahner, Sherr Elliott, Yiyan Ruan, Cyril Mignot, Boris Keren, Hua Xie, Xiaoyan Wang, Bernt Popp, Christiane Zweier, Juliette Piard, Christine Coubes, Frederic Tran Mau-Them, Hana Safraou, A Micheil Innes, Julie Gauthier, Jacques L Michaud, Daniel C Koboldt, Odent Sylvie, Marjolaine Willems, Wen-Hann Tan, Benjamin Cogne, Claudine Rieubland, Dominique Braun, Scott Douglas McLean, Konrad Platzer, Pia Zacher, Henry Oppermann, Lucie Evenepoel, Pierre Blanc, Laïla El Khattabi, Neshatul Haque, Nikita R Dsouza, Michael T Zimmermann, Raul Urrutia, Eric W Klee, Yiping Shen, Hongzhen Du, Leonard Rappaport, Chang-Mei Liu, Xiaoli Chen","doi":"10.1016/j.ajhg.2024.09.006","DOIUrl":"10.1016/j.ajhg.2024.09.006","url":null,"abstract":"<p><p>Microtubule affinity-regulating kinase 2 (MARK2) contributes to establishing neuronal polarity and developing dendritic spines. Although large-scale sequencing studies have associated MARK2 variants with autism spectrum disorder (ASD), the clinical features and variant spectrum in affected individuals with MARK2 variants, early developmental phenotypes in mutant human neurons, and the pathogenic mechanism underlying effects on neuronal development have remained unclear. Here, we report 31 individuals with MARK2 variants and presenting with ASD, other neurodevelopmental disorders, and distinctive facial features. Loss-of-function (LoF) variants predominate (81%) in affected individuals, while computational analysis and in vitro expression assay of missense variants supported the effect of MARK2 loss. Using proband-derived and CRISPR-engineered isogenic induced pluripotent stem cells (iPSCs), we show that MARK2 loss leads to early neuronal developmental and functional deficits, including anomalous polarity and dis-organization in neural rosettes, as well as imbalanced proliferation and differentiation in neural progenitor cells (NPCs). Mark2^+/- mice showed abnormal cortical formation and partition and ASD-like behavior. Through the use of RNA sequencing (RNA-seq) and lithium treatment, we link MARK2 loss to downregulation of the WNT/β-catenin signaling pathway and identify lithium as a potential drug for treating MARK2-associated ASD.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2392-2410"},"PeriodicalIF":5.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline ATM sequence variants.","authors":"Marcy E Richardson, Megan Holdren, Terra Brannan, Miguel de la Hoya, Amanda B Spurdle, Sean V Tavtigian, Colin C Young, Lauren Zec, Susan Hiraki, Michael J Anderson, Logan C Walker, Shannon McNulty, Clare Turnbull, Marc Tischkowitz, Katherine Schon, Thomas Slavin, William D Foulkes, Melissa Cline, Alvaro N Monteiro, Tina Pesaran, Fergus J Couch","doi":"10.1016/j.ajhg.2024.08.022","DOIUrl":"10.1016/j.ajhg.2024.08.022","url":null,"abstract":"<p><p>The ClinGen Hereditary Breast, Ovarian, and Pancreatic Cancer (HBOP) Variant Curation Expert Panel (VCEP) is composed of internationally recognized experts in clinical genetics, molecular biology, and variant interpretation. This VCEP made specifications for the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP) guidelines for the ataxia telangiectasia mutated (ATM) gene according to the ClinGen protocol. These gene-specific rules for ATM were modified from the ACMG/AMP guidelines and were tested against 33 ATM variants of various types and classifications in a pilot curation phase. The pilot revealed a majority agreement between the HBOP VCEP classifications and the ClinVar-deposited classifications. Six pilot variants had conflicting interpretations in ClinVar, and re-evaluation with the VCEP's ATM-specific rules resulted in four that were classified as benign, one as likely pathogenic, and one as a variant of uncertain significance (VUS) by the VCEP, improving the certainty of interpretations in the public domain. Overall, 28 of the 33 pilot variants were not VUS, leading to an 85% classification rate. The ClinGen-approved, modified rules demonstrated value for improved interpretation of variants in ATM.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2411-2426"},"PeriodicalIF":5.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Homozygous variants in WDR83OS lead to a neurodevelopmental disorder with hypercholanemia.","authors":"Scott Barish, Sheng-Jia Lin, Reza Maroofian, Alper Gezdirici, Hamoud Alhebby, Aurélien Trimouille, Marta Biderman Waberski, Tadahiro Mitani, Ilka Huber, Kristian Tveten, Øystein L Holla, Øyvind L Busk, Henry Houlden, Ehsan Ghayoor Karimiani, Mehran Beiraghi Toosi, Reza Shervin Badv, Paria Najarzadeh Torbati, Fatemeh Eghbal, Javad Akhondian, Ayat Al Safar, Abdulrahman Alswaid, Giovanni Zifarelli, Peter Bauer, Dana Marafi, Jawid M Fatih, Kevin Huang, Cassidy Petree, Daniel G Calame, Charlotte von der Lippe, Fowzan S Alkuraya, Sami Wali, James R Lupski, Gaurav K Varshney, Jennifer E Posey, Davut Pehlivan","doi":"10.1016/j.ajhg.2024.10.002","DOIUrl":"10.1016/j.ajhg.2024.10.002","url":null,"abstract":"<p><p>WD repeat domain 83 opposite strand (WDR83OS) encodes the 106-aa (amino acid) protein Asterix, which heterodimerizes with CCDC47 to form the PAT (protein associated with ER translocon) complex. This complex functions as a chaperone for large proteins containing transmembrane domains to ensure proper folding. Until recently, little was known about the role of WDR83OS or CCDC47 in human disease traits. However, biallelic variants in CCDC47 were identified in four unrelated families with trichohepatoneurodevelopmental syndrome, characterized by a neurodevelopmental disorder (NDD) with liver dysfunction. Three affected siblings in an additional family share a homozygous truncating WDR83OS variant and a phenotype of NDD, dysmorphic features, and liver dysfunction. Using family-based rare variant analyses of exome sequencing (ES) data and case matching through GeneMatcher, we describe the clinical phenotypes of 11 additional individuals in eight unrelated families (nine unrelated families, 14 individuals in total) with biallelic putative truncating variants in WDR83OS. Consistent clinical features include NDD (14/14), facial dysmorphism (13/14), intractable itching (9/14), and elevated bile acids (5/6). Whereas bile acids were significantly elevated in 5/6 of individuals tested, bilirubin was normal and liver enzymes were normal to mildly elevated in all 14 individuals. In three of six individuals for whom longitudinal data were available, we observed a progressive reduction in relative head circumference. A zebrafish model lacking Wdr83os function further supports its role in the nervous system, craniofacial development, and lipid absorption. Taken together, our data support a disease-gene association between biallelic loss-of-function of WDR83OS and a neurological disease trait with hypercholanemia.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2566-2581"},"PeriodicalIF":8.1,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotypic spectrum of dual diagnoses in developmental disorders.","authors":"Alys M Ridsdale, Anna Dickerson, V Kartik Chundru, Helen V Firth, Caroline F Wright","doi":"10.1016/j.ajhg.2024.08.025","DOIUrl":"10.1016/j.ajhg.2024.08.025","url":null,"abstract":"<p><p>As more patients receive genome-wide sequencing, the number of individuals diagnosed with multiple monogenic conditions is increasing. We sought to investigate the relative phenotypic contribution of dual diagnoses using both manual curation and computational approaches. First, we computed 1,003,236 semantic similarity scores for all possible pairs of 1,417 genes in the Developmental Disorder Gene2Phenotype (DDG2P) database using Human Phenotype Ontology terms. Next, for 62 probands with two molecular diagnoses in the Deciphering Developmental Disorders study, we computed semantic similarity scores between the probands' phenotypes and DDG2P phenotypes associated with the two disorders and compared the results with manual attribution of proband phenotypes to none, one, or both of the genes. We found a spectrum of phenotypic similarity for dual diagnoses, both across all DDG2P genes and within dual diagnosed probands, from phenotypically distinct through blended to indistinguishable conditions. Pairwise semantic similarity scores between two DDG2P genes were a good predictor of the extent of phenotypic blending observed in probands. Dual diagnoses involving genes linked with synergistic phenotypes can result in more extreme presentations while those involving antagonistic phenotypes have spuriously high pairwise semantic similarity scores despite a potentially milder atypical presentation. We suggest that the phenotypic contribution of two molecular diagnoses may contain discrete, synergistic, or antagonistic elements. Conceptual recognition of this phenotypic spectrum is important for making a final clinico-molecular diagnosis and providing accurate genetic counseling.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2382-2391"},"PeriodicalIF":5.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling recent positive selection using identity-by-descent segments.","authors":"Seth D Temple, Ryan K Waples, Sharon R Browning","doi":"10.1016/j.ajhg.2024.08.023","DOIUrl":"10.1016/j.ajhg.2024.08.023","url":null,"abstract":"<p><p>Recent positive selection can result in an excess of long identity-by-descent (IBD) haplotype segments overlapping a locus. The statistical methods that we propose here address three major objectives in studying selective sweeps: scanning for regions of interest, identifying possible sweeping alleles, and estimating a selection coefficient s. First, we implement a selection scan to locate regions with excess IBD rates. Second, we estimate the allele frequency and location of an unknown sweeping allele by aggregating over variants that are more abundant in an inferred outgroup with excess IBD rate versus the rest of the sample. Third, we propose an estimator for the selection coefficient and quantify uncertainty using the parametric bootstrap. Comparing against state-of-the-art methods in extensive simulations, we show that our methods are more precise at estimating s when s≥0.015. We also show that our 95% confidence intervals contain s in nearly 95% of our simulations. We apply these methods to study positive selection in European ancestry samples from the Trans-Omics for Precision Medicine project. We analyze eight loci where IBD rates are more than four standard deviations above the genome-wide median, including LCT where the maximum IBD rate is 35 standard deviations above the genome-wide median. Overall, we present robust and accurate approaches to study recent adaptive evolution without knowing the identity of the causal allele or using time series data.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2510-2529"},"PeriodicalIF":5.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Where is the boundary of the human pseudoautosomal region?","authors":"Daniel W Bellott, Jennifer F Hughes, Helen Skaletsky, Erik C Owen, David C Page","doi":"10.1016/j.ajhg.2024.09.005","DOIUrl":"10.1016/j.ajhg.2024.09.005","url":null,"abstract":"<p><p>A recent publication describing the assembly of the Y chromosomes of 43 males was remarkable not only for its ambitious technical scope but also for the startling suggestion that the boundary of the pseudoautosomal region 1 (PAR1), where the human X and Y chromosomes engage in crossing-over during male meiosis, lies 500 kb distal to its previously reported location. Where is the boundary of the human PAR1? We first review the evidence that mapped the PAR boundary, or PAB, before the human genome draft sequence was produced, then examine post-genomic datasets for evidence of crossing-over between the X and Y, and lastly re-examine contiguous sequence assemblies of the PAR-NPY boundary to see whether they support a more distal PAB. We find ample evidence of X-Y crossovers throughout the 500 kb in question, some as close as 246 bp to the previously reported PAB. Our new analyses, combined with previous studies over the past 40 years, provide overwhelming evidence to support the original position and narrow the probable location of the PAB to a 201-bp window.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"2530-2541"},"PeriodicalIF":5.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}