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We describe the variation in copy number of a ~ 10 kb region overlapping the long intergenic noncoding RNA (lincRNA) gene, TTTY22, within the IR3 inverted repeat on the short arm of the human Y chromosome, leading to individuals with 0–3 copies of this region in the general population. Variation of this CNV is common, with 266 individuals having 0 copies, 943 (including the reference sequence) having 1, 23 having 2 copies, and two having 3 copies, and was validated by breakpoint PCR, fibre-FISH, and 10× Genomics Chromium linked-read sequencing in subsets of 1234 individuals from the 1000 Genomes Project. Mapping the changes in copy number to the phylogeny of these Y chromosomes previously established by the Project identified at least 20 mutational events, and investigation of flanking paralogous sequence variants showed that the mutations involved flanking sequences in 18 of these, and could extend over > 30 kb of DNA. While either gene conversion or double crossover between misaligned sister chromatids could formally explain the 0–2 copy events, gene conversion is the more likely mechanism, and these events include the longest non-allelic gene conversion reported thus far. Chromosomes with three copies of this CNV have arisen just once in our data set via another mechanism: duplication of 420 kb that places the third copy 230 kb proximal to the existing proximal copy. Our results establish gene conversion as a previously under-appreciated mechanism of generating copy number changes in humans and reveal the exceptionally large size of the conversion events that can occur. [ABSTRACT FROM AUTHOR]

We have analyzed eight Y-chromosomal binary markers (YAP, RPS4Y711, M9, M175, LINE1, SRY+465, 47z, and M95) and three Y-STR markers (DYS390, DYS391, and DYS393) in 738 males from 11 ethnic groups in east Asia in order to study the male lineage history of Korea. Haplogroup DE-YAP was found at a high frequency only in Japan but was also present at low frequencies in northeast Asia, including 2.5% in Korea, suggesting a northern origin for these chromosomes. Haplogroup C-RPS4Y711 was present in Korea and Manchuria at moderate frequencies: higher than in populations from southeast Asia, but lower than those in the northeast, which may imply a northern Asian expansion of these lineages, perhaps from Mongolia or Siberia. The major Y-chromosomal expansions in east Asia were those of haplogroup O-M175 (and its sublineages). This haplogroup is likely to have originated in southern east Asia and subsequently expanded to all of east Asia. The moderate frequency of one sublineage in the Koreans, haplogroup O-LINE1 (12.5%), could be a result of interaction with Chinese populations. The age of another sublineage, haplogroup O-SRY+465, and Y-STR haplotype diversity provide evidence for relatively recent male migration, originally from China, through Korea into Japan. In conclusion, the distribution pattern of Y-chromosomal haplogroups reveals the complex origin of the Koreans, resulting from genetic contributions involving the northern Asian settlement and range expansions mostly from southern-to-northern China. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) has become a significant health concern with an increasing rate of morbidity and mortality worldwide. India ranks second in the number of diabetes cases in the world. The increasing burden of DM can be explained by genetic predisposition of Indians to type 2 diabetes mellitus (T2DM) coupled with rapid urbanization and socio-economic development in the last 3 decades leading to drastic changes in lifestyle. Environment and lifestyle changes contribute to T2DM development by altering epigenetic processes such as DNA methylation, histone post-translational modifications, and long non-coding RNAs, all of which regulate chromatin structure and gene expression. Although the genetic predisposition of Indians to T2DM is well established, how environmental and genetic factors interact and lead to T2DM is not well understood. In this review, we discuss the prevalence of diabetes and its complications across different states in India and how various risk factors contribute to its pathogenesis. The review also highlights the role of genetic predisposition among the Indian population and epigenetic factors involved in the etiology of diabetes. Lastly, we review current treatments and emphasize the knowledge gap with respect to genetic and epigenetic factors in the Indian context. Further understanding of the genetic and epigenetic determinants will help in risk prediction and prevention as well as therapeutic interventions, which will improve the clinical management of diabetes and associated macro- and micro-vascular complications. [ABSTRACT FROM AUTHOR]

Brain arteriovenous malformation (BAVM) is a rare but serious cerebrovascular disease whose pathogenesis has not been fully elucidated. Studies have found that epigenetic regulation, genetic variation and their signaling pathways, immune inflammation, may be the cause of BAVM the main reason. This review comprehensively analyzes the key pathways and inflammatory factors related to BAVMs, and explores their interplay with epigenetic regulation and genetics. Studies have found that epigenetic regulation such as DNA methylation, non-coding RNAs and m6A RNA modification can regulate endothelial cell proliferation, apoptosis, migration and damage repair of vascular malformations through different target gene pathways. Gene defects such as KRAS, ACVRL1 and EPHB4 lead to a disordered vascular environment, which may promote abnormal proliferation of blood vessels through ERK, NOTCH, mTOR, Wnt and other pathways. PDGF-B and PDGFR-β were responsible for the recruitment of vascular adventitial cells and smooth muscle cells in the extracellular matrix environment of blood vessels, and played an important role in the pathological process of BAVM. Recent single-cell sequencing data revealed the diversity of various cell types within BAVM, as well as the heterogeneous expression of vascular-associated antigens, while neutrophils, macrophages and cytokines such as IL-6, IL-1, TNF-α, and IL-17A in BAVM tissue were significantly increased. Currently, there are no specific drugs targeting BAVMs, and biomarkers for BAVM formation, bleeding, and recurrence are lacking clinically. Therefore, further studies on molecular biological mechanisms will help to gain insight into the pathogenesis of BAVM and develop potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

Migration and admixture history of populations have always been curious and an interesting theme. The West Coast of India harbours a rich diversity, bestowing various ethno-linguistic groups, with many of them having well-documented history of migrations. The Roman Catholic is one such distinct group, whose origin was much debated. While some historians and anthropologists relating them to ancient group of Gaud Saraswat Brahmins, others relating them for being members of the Jews Lost Tribes in the first Century migration to India. Historical records suggests that this community was later forcibly converted to Christianity by the Portuguese in Goa during the Sixteenth Century. Till date, no genetic study was done on this group to infer their origin and genetic affinity. Hence, we analysed 110 Roman Catholics from three different locations of West Coast of India including Goa, Kumta and Mangalore using both uniparental and autosomal markers to understand their genetic history. We found that the Roman Catholics have close affinity with the Indo-European linguistic groups, particularly Brahmins. Additionally, we detected genetic signal of Jews in the linkage disequilibrium-based admixture analysis, which was absent in other Indo-European populations, who are inhabited in the same geographical regions. Haplotype-based analysis suggests that the Roman Catholics consist of South Asian-specific ancestry and showed high drift. Ancestry-specific historical population size estimation points to a possible bottleneck around the time of Goan inquisition (fifteenth century). Analysis of the Roman Catholics data along with ancient DNA data of Neolithic and bronze age revealed that the Roman Catholics fits well in a basic model of ancient ancestral composition, typical of most of the Indo-European caste groups of India. Mitochondrial DNA (mtDNA) analysis suggests that most of the Roman Catholics have aboriginal Indian maternal genetic ancestry; while the Y chromosomal DNA analysis indicates high frequency of R1a lineage, which is predominant in groups with higher ancestral North Indian (ANI) component. Therefore, we conclude that the Roman Catholics of Goa, Kumta and Mangalore regions are the remnants of very early lineages of Brahmin community of India, having Indo-Europeans genetic affinity along with cryptic Jewish admixture, which needs to be explored further., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Primary immunodeficiencies (PID) are a diverse group of genetic disorders caused by inadequate development and function of immune system. Identifying genetic etiology is important for genetic counselling and treatment decisions. Clinical relevance of genetic variants is a complex problem depending on gene-specific and variant specific genotype-phenotype interactions. To address this challenge, we aimed to characterize the pathogenic landscape of PID genes by combining the analysis of germline variations reported in ClinVar and HGMD ®  and identification of damaging variations available in dbSNP. We generated a joint ClinVar/HGMD database, which included 111,940 variants, among them 32,452 were classified as pathogenic/likely pathogenic. From a total of 5,415,794 bi- or multiallelic variants in PID genes recorded in dbSNP, we retrieved 38,291 high impact (HI) biallelic variants with presumably disruptive impact in the protein, of them 25,500 variants were not present in ClinVar/HGMD. Using a functional prediction algorithm, we additionally identified 28,507 deleterious and 56,016 neutral missense variants among dbSNP variants and created a collection of damaging and neutral variations in PID genes, not currently present in ClinVar/HGMD, with their allele frequencies and mappings to protein domains. The distribution of pathogenic variants from ClinVar/HGMD, HI variants and deleterious missense variants from dbSNP was analyzed in the context of hereditary pattern and gene specific metrics, such as pLI and haploinsufficiency. Our report summarized data on complex gene-specific variability in PID genes and might be useful for the identification of the most promising variants and gene regions for further study., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We provide the first whole genome Copy Number Variant (CNV) study addressing Roma, along with reference populations from South Asia, the Middle East and Europe. Using CNV calling software for short-read sequence data, we identified 3171 deletions and 489 duplications. Taking into account the known population history of the Roma, as inferred from whole genome nucleotide variation, we could discern how this history has shaped CNV variation. As expected, patterns of deletion variation, but not duplication, in the Roma followed those obtained from single nucleotide polymorphisms (SNPs). Reduced effective population size resulting in slightly relaxed natural selection may explain our observation of an increase in intronic (but not exonic) deletions within Loss of Function (LoF)-intolerant genes. Over-representation analysis for LoF-intolerant gene sets hosting intronic deletions highlights a substantial accumulation of shared biological processes in Roma, intriguingly related to signaling, nervous system and development features, which may be related to the known profile of private disease in the population. Finally, we show the link between deletions and known trait-related SNPs reported in the genome-wide association study (GWAS) catalog, which exhibited even frequency distributions among the studied populations. This suggests that, in general human populations, the strong association between deletions and SNPs associated to biomedical conditions and traits could be widespread across continental populations, reflecting a common background of potentially disease/trait-related CNVs. [ABSTRACT FROM AUTHOR]

The suite of phenotypic diversity across geographically distributed human populations is the outcome of genetic drift, gene flow, and natural selection throughout human evolution. Human genetic variation underlying local biological adaptations to selective pressures is incompletely characterized. With the emergence of population genetics modeling of large-scale genomic data derived from diverse populations, scientists are able to map signatures of natural selection in the genome in a process known as selection mapping. Inferred selection signals further can be used to identify candidate functional alleles that underlie putative adaptive phenotypes. Phenotypic association, fine mapping, and functional experiments facilitate the identification of candidate adaptive alleles. Functional investigation of candidate adaptive variation using novel techniques in molecular biology is slowly beginning to unravel how selection signals translate to changes in biology that underlie the phenotypic spectrum of our species. In addition to informing evolutionary hypotheses of adaptation, the discovery and functional annotation of adaptive alleles also may be of clinical significance. While selection mapping efforts in non-European populations are growing, there remains a stark under-representation of diverse human populations in current public genomic databases, of both clinical and non-clinical cohorts. This lack of inclusion limits the study of human biological variation. Identifying and functionally validating candidate adaptive alleles in more global populations is necessary for understanding basic human biology and human disease.

Males and females display biological differences that lead to a higher variance of offspring number in males, and this is frequently exacerbated in human societies by mating practices, and possibly by past socio-cultural circumstances. This implies that the genetic record might contain the imprint of past male-mediated expansions, which can be investigated by analysing the male-specific region of the Y chromosome (MSY). Here, we review studies that have used MSY data to infer such expansions. Sets of short-tandem repeats define haplotypes of very low average frequencies, but in a few cases, high-frequency haplotypes are observed, forming the core of descent clusters. Estimates of the ages of such clusters, together with geographical information, have been used to propose powerful historical founders, including Genghis Khan, although without direct supporting evidence. Resequencing of multi-megabase segments of MSY has allowed the construction of detailed phylogenies in which branch lengths are proportional to time, leading to the identification of lineage expansions in the last few millennia as well as the more distant past. Comparisons with maternally-inherited mitochondrial DNA sequence data allow the male specificity of some of these expansions to be demonstrated. These include expansions in Europe in the last ~5000 years that may be associated with a cultural shift during the Bronze Age, as well as expansions elsewhere in the world for which explanations from archaeological evidence are not yet clear. [ABSTRACT FROM AUTHOR]

The human Y chromosome provides a fertile ground for structural rearrangements owing to its haploidy and high content of repeated sequences. The methodologies used for copy number variation (CNV) studies have developed over the years. Low-throughput techniques based on direct observation of rearrangements were developed early on, and are still used, often to complement array-based or sequencing approaches which have limited power in regions with high repeat content and specifically in the presence of long, identical repeats, such as those found in human sex chromosomes. Some specific rearrangements have been investigated for decades; because of their effects on fertility, or their outstanding evolutionary features, the interest in these has not diminished. However, following the flourishing of large-scale genomics, several studies have investigated CNVs across the whole chromosome. These studies sometimes employ data generated within large genomic projects such as the DDD study or the 1000 Genomes Project, and often survey large samples of healthy individuals without any prior selection. Novel technologies based on sequencing long molecules and combinations of technologies, promise to stimulate the study of Y-CNVs in the immediate future. [ABSTRACT FROM AUTHOR]

Estimating the effects of variants found in disease driver genes opens the door to personalized therapeutic opportunities. Clinical associations and laboratory experiments can only characterize a tiny fraction of all the available variants, leaving the majority as variants of unknown significance (VUS). In silico methods bridge this gap by providing instant estimates on a large scale, most often based on the numerous genetic differences between species. Despite concerns that these methods may lack reliability in individual subjects, their numerous practical applications over cohorts suggest they are already helpful and have a role to play in genome interpretation when used at the proper scale and context. In this review, we aim to gain insights into the training and validation of these variant effect predicting methods and illustrate representative types of experimental and clinical applications. Objective performance assessments using various datasets that are not yet published indicate the strengths and limitations of each method. These show that cautious use of in silico variant impact predictors is essential for addressing genome interpretation challenges. [ABSTRACT FROM AUTHOR]

Trypsinogen (PRSS1, PRSS2) copy number gains and regulatory variants have both been proposed to elevate pancreatitis risk through a gene dosage effect (i.e., by increasing the expression of wild-type protein). However, to date, their impact on pancreatitis risk has not been thoroughly evaluated whilst the underlying pathogenic mechanisms remain to be explicitly investigated in mouse models. Genetic studies of the rare trypsinogen duplication and triplication copy number variants (CNVs), and the common rs10273639C variant, were collated from PubMed and/or ClinVar. Mouse studies that analyzed the influence of a transgenically expressed wild-type human PRSS1 or PRSS2 gene on the development of pancreatitis were identified from PubMed. The genetic effects of the different risk genotypes, in terms of odds ratios, were calculated wherever appropriate. The genetic effects of the rare trypsinogen duplication and triplication CNVs were also evaluated by reference to their associated disease subtypes. We demonstrate a positive correlation between increased trypsinogen gene dosage and pancreatitis risk in the context of the rare duplication and triplication CNVs, and between the level of trypsinogen expression and disease risk in the context of the heterozygous and homozygous rs10273639C-tagged genotypes. We retrospectively identify three mouse transgenic studies that are informative in relation to the pathogenic mechanism underlying the trypsinogen gene dosage effect in pancreatitis. Trypsinogen gene dosage correlates with pancreatitis risk across genetic and transgenic studies, highlighting the fundamental role of dysregulated expression of wild-type trypsinogen in the etiology of pancreatitis. Specifically downregulating trypsinogen expression in the pancreas may serve as a potential therapeutic and/or prevention strategy for pancreatitis. [ABSTRACT FROM AUTHOR]

Epistatic interactions complicate the identification of variants involved in phenotypic effect. In-depth knowledge in modifiers and in pathogenic variants would benefit the mechanistic studies on the genetic basis of complex traits. We systematically compared the modifier variants which have evidence of modifier effect with the pathogenic variants from multiple angles. Our study found that genomic loci of modifier variations differ from pathogenic loci in many aspects, such as population genetics statistics, epigenetic features, evolutionary characteristics and functional properties of the variations. Genes containing modifier variation(s) exhibit higher probability of being haploinsufficient and higher probability of recessive disease causation, and they are relatively more important in network communication. Furthermore, we reinforced that co-expression analysis is an effective methodology to predict functional associations between modifier genes and their potential target genes. In many aspects, we detected statistically significant differences between modifier variants/genes and pathogenic variants/genes, and investigated relationships between modifiers and their potential targets. Our results offer some actionable insights that may provide appropriate guidelines to clinical genetics and researchers to elucidate the molecular mechanism underlying the human phenotypic variation. [ABSTRACT FROM AUTHOR]

To test for human population substructure and to investigate human population history we have analysed Y-chromosome diversity using seven microsatellites (Y-STRs) and ten binary markers (Y-SNPs) in samples from eight regionally distributed populations from Poland ( n=913) and 11 from Germany ( n=1,215). Based on data from both Y-chromosome marker systems, which we found to be highly correlated ( r=0.96), and using spatial analysis of the molecular variance (SAMOVA), we revealed statistically significant support for two groups of populations: (1) all Polish populations and (2) all German populations. By means of analysis of the molecular variance (AMOVA) we observed a large and statistically significant proportion of 14% (for Y-SNPs) and 15% (for Y-STRs) of the respective total genetic variation being explained between both countries. The same population differentiation was detected using Monmonier’s algorithm, with a resulting genetic border between Poland and Germany that closely resembles the course of the political border between both countries. The observed genetic differentiation was mainly, but not exclusively, due to the frequency distribution of two Y-SNP haplogroups and their associated Y-STR haplotypes: R1a1*, most frequent in Poland, and R1*(xR1a1), most frequent in Germany. We suggest here that the pronounced population differentiation between the two geographically neighbouring countries, Poland and Germany, is the consequence of very recent events in human population history, namely the forced human resettlement of many millions of Germans and Poles during and, especially, shortly after World War II. In addition, our findings have consequences for the forensic application of Y-chromosome markers, strongly supporting the implementation of population substructure into forensic Y chromosome databases, and also for genetic association studies. [ABSTRACT FROM AUTHOR]

Structural variation includes a change in copy number, orientation, or location of a part of the genome. Copy number variants (CNVs) are a common cause of genetic hearing loss, comprising nearly 20% of diagnosed cases. While large deletions involving the gene STRC are the most common pathogenic CNVs, a significant proportion of known hearing loss genes also contain pathogenic CNVs. In this review, we provide an overview of currently used methods for detection of CNVs in genes known to cause hearing loss including molecular techniques such as multiplex ligation probe amplification (MLPA) and digital droplet polymerase chain reaction (ddPCR), array-CGH and single-nucleotide polymorphism (SNP) arrays, as well as techniques for detection of CNVs using next-generation sequencing data analysis including targeted gene panel, exome, and genome sequencing data. In addition, in this review, we compile published data on pathogenic hearing loss CNVs to provide an up-to-date overview. We show that CNVs have been identified in 29 different non-syndromic hearing loss genes. An understanding of the contribution of CNVs to genetic hearing loss is critical to the current diagnosis of hearing loss and is crucial for future gene therapies. Thus, evaluation for CNVs is required in any modern pipeline for genetic diagnosis of hearing loss. [ABSTRACT FROM AUTHOR]

Usher syndrome, the most prevalent cause of combined hereditary vision and hearing impairment, is clinically and genetically heterogeneous. Moreover, several conditions with phenotypes overlapping Usher syndrome have been described. This makes the molecular diagnosis of hereditary deaf–blindness challenging. Here, we performed exome sequencing and analysis on 7 Mexican and 52 Iranian probands with combined retinal degeneration and hearing impairment (without intellectual disability). Clinical assessment involved ophthalmological examination and hearing loss questionnaire. Usher syndrome, most frequently due to biallelic variants in MYO7A (USH1B in 16 probands), USH2A (17 probands), and ADGRV1 (USH2C in 7 probands), was diagnosed in 44 of 59 (75%) unrelated probands. Almost half of the identified variants were novel. Nine of 59 (15%) probands displayed other genetic entities with dual sensory impairment, including Alström syndrome (3 patients), cone-rod dystrophy and hearing loss 1 (2 probands), and Heimler syndrome (1 patient). Unexpected findings included one proband each with Scheie syndrome, coenzyme Q10 deficiency, and pseudoxanthoma elasticum. In four probands, including three Usher cases, dual sensory impairment was either modified/aggravated or caused by variants in distinct genes associated with retinal degeneration and/or hearing loss. The overall diagnostic yield of whole exome analysis in our deaf–blind cohort was 92%. Two (3%) probands were partially solved and only 3 (5%) remained without any molecular diagnosis. In many cases, the molecular diagnosis is important to guide genetic counseling, to support prognostic outcomes and decisions with currently available and evolving treatment modalities. [ABSTRACT FROM AUTHOR]

In order to attain a finer reconstruction of the peopling of southern and central-eastern Europe from the Levant, we determined the frequencies of eight lineages internal to the Y chromosomal haplogroup J, defined by biallelic markers, in 22 population samples obtained with a fine-grained sampling scheme. Our results partially resolve a major multifurcation of lineages within the haplogroup. Analyses of molecular variance show that the area covered by haplogroup J dispersal is characterized by a significant degree of molecular radiation for unique event polymorphisms within the haplogroup, with a higher incidence of the most derived sub-haplogroups on the northern Mediterranean coast, from Turkey westward; here, J diversity is not simply a subset of that present in the area in which this haplogroup first originated. Dating estimates, based on simple tandem repeat loci (STR) diversity within each lineage, confirmed the presence of a major population structuring at the time of spread of haplogroup J in Europe and a punctuation in the peopling of this continent in the post-Neolithic, compatible with the expansion of the Greek world. We also present here, for the first time, a novel method for comparative dating of lineages, free of assumptions of STR mutation rates. [ABSTRACT FROM AUTHOR]

A non-negligible proportion of human pathogenic variants are known to be present as wild type in at least some non-human mammalian species. The standard explanation for this finding is that molecular mechanisms of compensatory epistasis can alleviate the mutations' otherwise pathogenic effects. Examples of compensated variants have been described in the literature but the interacting residue(s) postulated to play a compensatory role have rarely been ascertained. In this study, the examination of five human X-chromosomally encoded proteins (FIX, GLA, HPRT1, NDP and OTC) allowed us to identify several candidate compensated variants. Strong evidence for a compensated/compensatory pair of amino acids in the coagulation FIXa protein (involving residues 270 and 271) was found in a variety of mammalian species. Both amino acid residues are located within the 60-loop, spatially close to the 39-loop that performs a key role in coagulation serine proteases. To understand the nature of the underlying interactions, molecular dynamics simulations were performed. The predicted conformational change in the 39-loop consequent to the Glu270Lys substitution (associated with hemophilia B) appears to impair the protein's interaction with its substrate but, importantly, such steric hindrance is largely mitigated in those proteins that carry the compensatory residue (Pro271) at the neighboring amino acid position. [ABSTRACT FROM AUTHOR]

Primary immunodeficiencies (PID) are a diverse group of genetic disorders caused by inadequate development and function of immune system. Identifying genetic etiology is important for genetic counselling and treatment decisions. Clinical relevance of genetic variants is a complex problem depending on gene-specific and variant specific genotype–phenotype interactions. To address this challenge, we aimed to characterize the pathogenic landscape of PID genes by combining the analysis of germline variations reported in ClinVar and HGMD® and identification of damaging variations available in dbSNP. We generated a joint ClinVar/HGMD database, which included 111,940 variants, among them 32,452 were classified as pathogenic/likely pathogenic. From a total of 5,415,794 bi- or multiallelic variants in PID genes recorded in dbSNP, we retrieved 38,291 high impact (HI) biallelic variants with presumably disruptive impact in the protein, of them 25,500 variants were not present in ClinVar/HGMD. Using a functional prediction algorithm, we additionally identified 28,507 deleterious and 56,016 neutral missense variants among dbSNP variants and created a collection of damaging and neutral variations in PID genes, not currently present in ClinVar/HGMD, with their allele frequencies and mappings to protein domains. The distribution of pathogenic variants from ClinVar/HGMD, HI variants and deleterious missense variants from dbSNP was analyzed in the context of hereditary pattern and gene specific metrics, such as pLI and haploinsufficiency. Our report summarized data on complex gene-specific variability in PID genes and might be useful for the identification of the most promising variants and gene regions for further study. [ABSTRACT FROM AUTHOR]

Trisomy is the leading known cause of mental retardation and pregnancy loss in humans, yet virtually nothing is known of the underlying nondisjunctional mechanisms. Since studies of other organisms suggest an association between centromere size or sequence and meiotic nondisjunction, we recently initiated studies to examine the effect of centromere size variation on human nondisjunction. In the present report, we summarize studies correlating variation in the size of the Y-chromosome centromere with sex chromosome nondisjunction. In one set of studies, we used pulsed-field gel electrophoresis to estimate Y-chromosome alpha-satellite array lengths in normal males, and correlated these values with Y-chromosome sperm disomy levels as determined by fluorescence in situ hybridization. In a second set of studies, we determined the Y-chromosome alpha-satellite array length of 47,XYY males, since the karyotypes of these individuals are a consequence of Y chromosome nondisjunction. Neither set of studies provided evidence for an effect of Y-chromosome alpha-satellite array length on Y-chromosome nondisjunction. Thus, if there is an association between Y-chromosome centromere size and nondisjunction, the effect is subtle and below the detection levels of the present study or involves extreme size variants that were not represented in the present study population. [ABSTRACT FROM AUTHOR]

Fetal growth is an important determinant of cardiometabolic disease risk during childhood and adulthood. The genetic architecture of fetal growth remains largely understudied in ancestrally diverse populations. We conducted genome-wide admixture mapping scan and analysis of genetic ancestry among Hispanic American, African American, European American, and Asian American pregnant women to identify genetic loci associated with fetal growth measures across 13–40 weeks gestation. Fetal growth measures were associated with genome-wide average African, European, Amerindigenous and East Asian ancestry proportions (P ranged from10−3 to 4.8 × 10–2). Admixture mapping analysis identified ten African ancestry loci and three Amerindigenous ancestry loci significantly associated with fetal growth measures at Bonferroni-corrected levels of significance (P ranged from 2.18 × 10–8 to 3.71 × 10–6). At the chr2q23.3–24.2 locus in which higher African ancestry was associated with long bone (femur and humerus) lengths, the T allele of rs13030825 (GALNT13) was associated with longer humerus length in African Americans (β = 0.44, P = 6.25 × 10–6 at week 27; β = 0.39, P = 7.72 × 10–5 at week 40). The rs13030825 SNP accounted for most of the admixture association at the chr2q23.3–24.2 locus and has substantial allele frequency difference between African and European reference samples (FST = 0.55, P = 0.03). Regulatory annotation shows that rs13030825 overlaps with the serum response factor (SRF) transcription factor previously implicated in postnatal bone development of mice. Overall, we identified ancestry-related maternal genetic loci that influence fetal growth, shedding light on molecular pathways that regulate fetal growth and potential effects on health across the lifespan. Clinical trials registration ClinicalTrials.gov, NCT00912132. [ABSTRACT FROM AUTHOR]

Copy number variation (CNV) related disorders tend to show complex phenotypic profiles that do not match known diseases. This makes it difficult to ascertain their underlying molecular basis. A potential solution is to compare the affected genomic regions for multiple patients that share a pathological phenotype, looking for commonalities. Here, we present a novel approach to associate phenotypes with functional systems, in terms of GO categories and KEGG and Reactome pathways, based on patient data. The approach uses genomic and phenomic data from the same patients, finding shared genomic regions between patients with similar phenotypes. These regions are mapped to genes to find associated functional systems. We applied the approach to analyse patients in the DECIPHER database with de novo CNVs, finding functional systems associated with most phenotypes, often due to mutations affecting related genes in the same genomic region. Manual inspection of the ten top-scoring phenotypes found multiple FunSys connections supported by the previous studies for seven of them. The workflow also produces reports focussed on the genes and FunSys connected to the different phenotypes, alongside patient-specific reports, which give details of the associated genes and FunSys for each individual in the cohort. These can be run in "confidential" mode, preserving patient confidentiality. The workflow presented here can be used to associate phenotypes with functional systems using data at the level of a whole cohort of patients, identifying important connections that could not be found when considering them individually. The full workflow is available for download, enabling it to be run on any patient cohort for which phenotypic and CNV data are available. [ABSTRACT FROM AUTHOR]

The Human Gene Mutation Database (HGMD®) constitutes a comprehensive collection of published germline mutations in nuclear genes that are thought to underlie, or are closely associated with human inherited disease. At the time of writing (June 2020), the database contains in excess of 289,000 different gene lesions identified in over 11,100 genes manually curated from 72,987 articles published in over 3100 peer-reviewed journals. There are primarily two main groups of users who utilise HGMD on a regular basis; research scientists and clinical diagnosticians. This review aims to highlight how to make the most out of HGMD data in each setting. [ABSTRACT FROM AUTHOR]

Malaria has been the pre-eminent cause of early mortality in many parts of the world throughout much of the last five thousand years and, as a result, it is the strongest force for selective pressure on the human genome yet described. Around one third of the variability in the risk of severe and complicated malaria is now explained by additive host genetic effects. Many individual variants have been identified that are associated with malaria protection, but the most important all relate to the structure or function of red blood cells. They include the classical polymorphisms that cause sickle cell trait, α-thalassaemia, G6PD deficiency, and the major red cell blood group variants. More recently however, with improving technology and experimental design, others have been identified that include the Dantu blood group variant, polymorphisms in the red cell membrane protein ATP2B4, and several variants related to the immune response. Characterising how these genes confer their effects could eventually inform novel therapeutic approaches to combat malaria. Nevertheless, all together, only a small proportion of the heritable component of malaria resistance can be explained by the variants described so far, underscoring its complex genetic architecture and the need for continued research. [ABSTRACT FROM AUTHOR]

Immune response is one of the functions that have been more strongly targeted by natural selection during human evolution. The evolutionary genetic dissection of the immune system has greatly helped to distinguish genes and functions that are essential, redundant or advantageous for human survival. It is also becoming increasingly clear that admixture between early Eurasians with now-extinct hominins such as Neanderthals or Denisovans, or admixture between modern human populations, can be beneficial for human adaptation to pathogen pressures. In this review, we discuss how the integration of population genetics with functional genomics in diverse human populations can inform about the changes in immune functions related to major lifestyle transitions (e.g., from hunting and gathering to farming), the action of natural selection to the evolution of the immune system, and the history of past epidemics. We also highlight the need of expanding the characterization of the immune system to a larger array of human populations—particularly neglected human groups historically exposed to different pathogen pressures—to fully capture the relative contribution of genetic, epigenetic, and environmental factors to immune response variation in humans. [ABSTRACT FROM AUTHOR]