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Fulltext Copy number variation arising from gene conversion on the human Y chromosome

Shi W, Massaia A, Louzada S, Banerjee R, Hallast P, Chen Y, et al.

Hum Genet, 2018 Jan;137(1):73-83.
PMID: 29209947 DOI: 10.1007/s00439-017-1857-9

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.

Matched MeSH terms: Chromosomes, Human, Y/genetics*
Y-chromosome and mitochondrial DNA studies on the population structure of the Christmas Island community

Wise CA, Sullivan SG, Black ML, Erber WN, Bittles AH

Am J Phys Anthropol, 2005 Nov;128(3):670-7.
PMID: 15864813

Christmas Island is a remote Australian territory located close to the main Indonesian island of Java. Y-chromosome and mitochondrial DNA (mtDNA) markers were used to investigate the genetic structure of the population, which comprises communities of mixed ethnic origin. Analysis of 12 Y-chromosome biallelic polymorphisms revealed a high level of gene diversity and haplotype frequencies that were consistent with source populations in southern China and Southeast Asia. mtDNA hypervariable segment I (HVS-I) sequences displayed high levels of haplotype diversity and nucleotide diversity that were comparable to various Asian populations. Genetic distances revealed extremely low mtDNA differentiation among Christmas Islanders and Asian populations. This was supported by the relatively high proportion of sequence types shared among these populations. The most common mtDNA haplogroups were M* and B, followed by D and F, which are prevalent in East/Southeast Asia. Christmas Islanders of European descent were characterized by the Eurasian haplogroup R*, and a limited degree of admixture was observed. In general, analysis of the genetic data indicated population affinities to southern Chinese (in particular from the Yunnan Province) and Southeast Asia (Thailand, Malaysia, and Cambodia), which was consistent with historical records of settlement. The combined use of these different marker systems provides a useful and appropriate model for the study of contemporary populations derived from different ethnic origins.

Matched MeSH terms: Chromosomes, Human, Y/genetics*
Fulltext Mitochondrial and Y-chromosome diversity of the Tharus (Nepal): a reservoir of genetic variation

Fornarino S, Pala M, Battaglia V, Maranta R, Achilli A, Modiano G, et al.

BMC Evol. Biol., 2009;9:154.
PMID: 19573232 DOI: 10.1186/1471-2148-9-154

Central Asia and the Indian subcontinent represent an area considered as a source and a reservoir for human genetic diversity, with many markers taking root here, most of which are the ancestral state of eastern and western haplogroups, while others are local. Between these two regions, Terai (Nepal) is a pivotal passageway allowing, in different times, multiple population interactions, although because of its highly malarial environment, it was scarcely inhabited until a few decades ago, when malaria was eradicated. One of the oldest and the largest indigenous people of Terai is represented by the malaria resistant Tharus, whose gene pool could still retain traces of ancient complex interactions. Until now, however, investigations on their genetic structure have been scarce mainly identifying East Asian signatures.

Matched MeSH terms: Chromosomes, Human, Y/genetics*
Fulltext Y Chromosome Sequences Reveal a Short Beringian Standstill, Rapid Expansion, and early Population structure of Native American Founders

Pinotti T, Bergström A, Geppert M, Bawn M, Ohasi D, Shi W, et al.

Curr Biol, 2019 01 07;29(1):149-157.e3.
PMID: 30581024 DOI: 10.1016/j.cub.2018.11.029

The Americas were the last inhabitable continents to be occupied by humans, with a growing multidisciplinary consensus for entry 15-25 thousand years ago (kya) from northeast Asia via the former Beringia land bridge [1-4]. Autosomal DNA analyses have dated the separation of Native American ancestors from the Asian gene pool to 23 kya or later [5, 6] and mtDNA analyses to ∼25 kya [7], followed by isolation ("Beringian Standstill" [8, 9]) for 2.4-9 ky and then a rapid expansion throughout the Americas. Here, we present a calibrated sequence-based analysis of 222 Native American and relevant Eurasian Y chromosomes (24 new) from haplogroups Q and C [10], with four major conclusions. First, we identify three to four independent lineages as autochthonous and likely founders: the major Q-M3 and rarer Q-CTS1780 present throughout the Americas, the very rare C3-MPB373 in South America, and possibly the C3-P39/Z30536 in North America. Second, from the divergence times and Eurasian/American distribution of lineages, we estimate a Beringian Standstill duration of 2.7 ky or 4.6 ky, according to alternative models, and entry south of the ice sheet after 19.5 kya. Third, we describe the star-like expansion of Q-M848 (within Q-M3) starting at 15 kya [11] in the Americas, followed by establishment of substantial spatial structure in South America by 12 kya. Fourth, the deep branches of the Q-CTS1780 lineage present at low frequencies throughout the Americas today [12] may reflect a separate out-of-Beringia dispersal after the melting of the glaciers at the end of the Pleistocene.

Matched MeSH terms: Chromosomes, Human, Y/genetics*
Association of azoospermia factor region deletions in infertile male subjects among Malaysians

Hussein AA, Vasudevan R, Patimah I, Prashant N, Nora FA

Andrologia, 2015 Mar;47(2):168-77.
PMID: 24528375 DOI: 10.1111/and.12240

Azoospermia factor region (AZF) deletions (AZFa, AZFb, AZFc and AZFd) in the Y chromosome were analysed in male infertility subjects in various populations with conflicting results. This study comprised of 54 infertile males and 63 fertile controls, and the frequency of AZFa, AZFb, AZFc and AZFd deletions were determined using conventional polymerase chain reaction (PCR) as well as real-time PCR-high resolution melting analysis-based methods. The results of this study showed that, three of 54 cases (5.55%) had AZF (a, b and c) deletions (two had AZFc and one had AZFa deletions). Four cases were found to have AZFd deletions (7.4%) with two of them being associated with AZFc deletions (P = 0.028). The frequency of AZF (a, b and c) deletions in Malaysian infertile male subjects was found to be comparable with other populations. AZFd deletions were found to be significant (P < 0.05) in male infertility and it may be associated with other types of AZF deletions.

Matched MeSH terms: Chromosomes, Human, Y/genetics*
Linkage between prostate cancer occurrence and Y-chromosomal DYS loci in Malaysian subjects

Nargesi MM, Ismail P, Razack AH, Pasalar P, Nazemi A, Oshkoor SA, et al.

Asian Pac J Cancer Prev, 2011;12(5):1265-8.
PMID: 21875279

PURPOSE: Prostate cancer differs markedly in incidence across ethnic groups. Since this disease is influenced by complex genetics, it is many genetic factors may affect the level of susceptibility to development of the disease. In this study, four Y-linked short tandem repeats (STRs), DYS388, DYS435, DYS437, and DYS439, were genotyped to compare Malaysian prostate cancer patients and normal control males.
MATERIALS AND METHODS: A total of 175 subjects comprising 84 patients and 91 healthy individuals were recruited. Multiplex PCR was optimized to co-amplify DYS388, DYS435, DYS437, and DYS439 loci. All samples were genotyped for alleles of four DYS loci using a Genetic Analysis System.
RESULTS: Of all DYS loci, allele 10 (A) of DYS388 had a significantly lower incidence of disease in compare with other alleles of this locus, while a higher incidence of disease was found among males who had either allele 12 (C) of DYS388 or allele 14 (E) of DYS439. Moreover, a total of 47 different haplotypes comprising different alleles of four DYS loci were found among the whole study samples, of which haplotypes AABC and CAAA showed a lower and higher frequency among cases than controls, respectively.
CONCLUSIONS: It is likely that Malaysian males who belong to Y-lineages with either allele 12 of DYS388, allele 14 of DYS439, or haplotype CAAA are more susceptible to develop prostate cancer, while those belonging to lineages with allele 10 of DYS388 or haplotype AABC are more resistant to the disease.

Matched MeSH terms: Chromosomes, Human, Y/genetics*
Fulltext Resolving the ancestry of Austronesian-speaking populations

Soares PA, Trejaut JA, Rito T, Cavadas B, Hill C, Eng KK, et al.

Hum Genet, 2016 Mar;135(3):309-26.
PMID: 26781090 DOI: 10.1007/s00439-015-1620-z

There are two very different interpretations of the prehistory of Island Southeast Asia (ISEA), with genetic evidence invoked in support of both. The "out-of-Taiwan" model proposes a major Late Holocene expansion of Neolithic Austronesian speakers from Taiwan. An alternative, proposing that Late Glacial/postglacial sea-level rises triggered largely autochthonous dispersals, accounts for some otherwise enigmatic genetic patterns, but fails to explain the Austronesian language dispersal. Combining mitochondrial DNA (mtDNA), Y-chromosome and genome-wide data, we performed the most comprehensive analysis of the region to date, obtaining highly consistent results across all three systems and allowing us to reconcile the models. We infer a primarily common ancestry for Taiwan/ISEA populations established before the Neolithic, but also detected clear signals of two minor Late Holocene migrations, probably representing Neolithic input from both Mainland Southeast Asia and South China, via Taiwan. This latter may therefore have mediated the Austronesian language dispersal, implying small-scale migration and language shift rather than large-scale expansion.

Matched MeSH terms: Chromosomes, Human, Y/genetics
Molecular characterization of a polymorphic 3-Mb deletion at chromosome Yp11.2 containing the AMELY locus in Singapore and Malaysia populations

Yong RY, Gan LS, Chang YM, Yap EP

Hum Genet, 2007 Nov;122(3-4):237-49.
PMID: 17588179

Amelogenin paralogs on Chromosome X (AMELX) and Y (AMELY) are commonly used sexing markers. Interstitial deletion of Yp involving the AMELY locus has previously been reported. The combined frequency of the AMELY null allele in Singapore and Malaysia populations is 2.7%, 0.6% in Indian and Malay ethnic groups respectively. It is absent among 541 Chinese screened. The null allele in this study belongs to 3 Y haplogroups; J2e1 (85.7%), F* (9.5%) and D* (4.8%). Low and high-resolution STS mapping, followed by sequence analysis of breakpoint junction confirmed a large deletion of 3 to 3.7-Mb located at the Yp11.2 region. Both breakpoints were located in TSPY repeat arrays, suggesting a non-allelic homologous recombination (NAHR) mechanism of deletion. All regional null samples shared identical breakpoint sequences according to their haplogroup affiliation, providing molecular evidence of a common ancestry origin for each haplogroup, and at least 3 independent deletion events recurred in history. The estimated ages based on Y-SNP and STR analysis were approximately 13.5 +/- 3.1 kyears and approximately 0.9 +/- 0.9 kyears for the J2e1 and F* mutations, respectively. A novel polymorphism G > A at Y-GATA-H4 locus in complete linkage disequilibrium with J2e1 null mutations is a more recent event. This work re-emphasizes the need to include other sexing markers for gender determination in certain regional populations. The frequency difference among global populations suggests it constitutes another structural variation locus of human chromosome Y. The breakpoint sequences provide further information to a better understanding of the NAHR mechanism and DNA rearrangements due to higher order genomic architecture.

Matched MeSH terms: Chromosomes, Human, Y/genetics*