Y chromosome haplogroups are associated with birth size in Japanese men.

The Y chromosome is classified into haplogroups (A-T) based on a combination of several DNA polymorphisms. Japanese men are mainly classified into haplogroups C, D, and O, which have been further subdivided. The distribution of Y-chromosome haplogroups varies by ethnicity. The phylogenetic age, origin, and migration also differ. I hypothesized that Y chromosome haplogroups may be associated with height and/or weight at birth. An association analysis of height and weight at birth with Y chromosome haplogroups was performed in 288 Japanese men. Men belonging to haplogroup O1b2 were significantly associated with short stature at birth (beta = －1.88, standard error (SE) = 0.55, P = 0.00076), and those belonging to D1a2a-12f2b were significantly associated with increased birth weight (beta = 174, SE = 64, P = 0.0069). Y chromosome haplogroups are associated with physical birth characteristics in modern Japanese men. J. Med. Invest. 71 : 129-133, February, 2024.

Genotype data for 60 SNP genetic markers associated with eye, hair, skin color, ABO blood group, sex, core Y-chromosome haplogroups in Kazakh population.

OBJECTIVES: The collection of genotype data was conducted as an essential part of a pivotal research project with the goal of examining the genetic variability of skin, hair, and iris color among the Kazakh population. The data has practical application in the field of forensic DNA phenotyping (FDA). Due to the limited size of forensic databases from Central Asia (Kazakhstan), it is practically impossible to obtain an individual identification result based on forensic profiling of short tandem repeats (STRs). However, the pervasive use of the FDA necessitates validation of the currently employed set of genetic markers in a variety of global populations. No such data existed for the Kazakhs. The Phenotype Expert kit (DNA Research Center, LLC, Russia) was used for the first time in this study to collect data. DATA DESCRIPTION: The present study provides genotype data for a total of 60 SNP genetic markers, which were analyzed in a sample of 515 ethnic Kazakhs. The dataset comprises a total of 41 single nucleotide polymorphisms (SNPs) obtained from the HIrisPlex-S panel. Additionally, there are 4 SNPs specifically related to the AB0 gene, 1 marker associated with the AMELX/Y genes, and 14 SNPs corresponding to the primary haplogroups of the Y chromosome. The aforementioned data could prove valuable to researchers with an interest in investigating genetic variability and making predictions about phenotype based on eye color, hair color, skin color, AB0 blood group, gender, and biogeographic origin within the male lineage.

Primary azoospermia factor C duplication associated with spermatogenic impariment: a case-control study based on Y-chromosome haplogrouping in a Han Chinese population.

BACKGROUND: Azoospermia factor C (AZFc) in the male-specific region of Y-chromosome (MSY) presents wide structure variation mainly due to frequent non-allele homologous recombination, leading to significant copy number variation of the AZFc-linked coding sequences involving in spermatogenesis. A large number of studies had been conducted to investigate the association between AZFc deletions and male infertility in certain Y chromosome genetic backgrounds, however, the influence of primary AZFc duplication on spermatogenesis remained controversial and the cause of the discrepant outcomes is unknown. METHODS: In the present study, a total of 1,102 unrelated Han Chinese males without any detectable AZF deletions were recruited from 2014 to 2019, including 411 controls with normozoospermia and 691 patients with idiopathic spermatogenic failure. Using multiple paralog ratio tests (PRTs), the structure duplications were classified by the copy number of the AZFc-linked amplicons and genes. The Y-chromosome haplogroup (Y-hg) was categorized by genetyping of MSY-linked polymorphism loci. The association of primary AZFc duplication with spermatogenic phenotype was investigated in males with the same Y-hg. RESULTS: Within Y-hg O3* group, the frequency of the gr/gr duplication in patients is significantly higher than that of controls (P = 1.29×10-3 , odds ratio (OR) 7.64, 95% confidence interval (CI) 1.79-32.57). Moreover, Y-hg O3* males with the gr/gr duplication presented a significantly lower sperm production compared with non-AZFc duplicated ones (sperm concentration: P = 1.46×10-3 ; total sperm count: P = 1.82 ×10-3 ). The b2/b3 duplication were identified clustered in Y-hg Cα2*, and the significant difference in the distribution was not observed between patients with spermatogenic failure and controls. CONCLUSION: The results suggest that, in the Han Chinese population, the gr/gr duplication is a predisposing genetic factor for spermatogenic impairment in males harboring Y-hg O3* . Meanwhile, the b2/b3 duplication may be fixed on a yet-unidentified subbranch of Y-hg Cα2* without significantly deleterious effect on spermatogenesis. Our findings provide evidence that the difference in the Y-hg composition may cause the discrepancy on the association of AZFc duplication with spermatogenic failure among the studied populations.

[DNA Phenotyping of Remains from Elite Burials of the Khazar Period of Southern Russia].

Ancient DNA analyses help to solve the problems related to the genogeographic origin and migration patterns of populations. The Khazar Khaganate is a subject of controversy among researchers. Its complex historical development, lack of a sufficient number of artistic and written sources, the disappearance of representatives of Khazar culture leaves open the question of the appearance of the Khazars. DNA phenotyping of bone remains from elite burials of the Khazar period of Southern Russia was carried out with respect to eye color, hair color, skin color, and AB0 blood groups. Eight out of 10 individuals had brown eyes, dark hair (to varying degrees), and a predominantly dark skin during their lifetime. Individuals from two burials had gray-blue eyes, and one individual had blond hair. The most probable AB0 blood group was identified in eight people, of which five blood group 0 (I) group, four had blood group A (II), and one had blood group B (III). The allele frequency distribution was assessed for ten population-specific autosomal markers and suggested high heterogeneity for the ethnogeographic origin of the Khazars examined. The results are evidence for ethnocultural, genetic, and phenotypic diversity of the Khazar Khaganate.

[A Biochip for Genotyping Polymorphisms Associated with Eye, Hair, Skin Color, AB0 Blood Group, Sex, Y Chromosome Core Haplogroup, and Its Application to Study the Slavic Population].

This paper presents a method for genotyping a panel of 60 single nucleotide polymorphisms (SNPs) using single-stage PCR followed by hybridization on a hydrogel biochip. The pool of analyzed polymorphisms consists of 41 SNPs included in the HIrisPlex-S panel, 4 SNPs of the AB0 gene (261G>Del, 297A>G, 657C>T, 681G>A), markers of the AMELX and AMELY genes, and 14 SNP markers of the Y chromosome haplogroups: B (M60), C (M130), D (CTS3946), E (M5388), G (P257), H (M2920), I (U179), J (M304), L (M185), N (M231), O (M175), Q (M1105), R (P224) and T (M272). These genetic data allow one to predict the phenotype of the desired person according to the characteristics of eye, hair, skin color, AB0 blood group, sex, and genogeographic origin in the male line. The setting protocol is simplified as much as possible to facilitate the introduction of the method into practice. The distribution of allele frequencies of the studied polymorphisms, as well as AB0 blood groups among the Slavs (N = 482), originating mainly from central Russia, was established.

Differences in DYF387S1 copy number distribution among haplogroups caused by haplogroup-specific ancestral Y-chromosome mutations.

DYF387S1 is a major Y-chromosome short tandem repeat (Y-STR) used in forensic genetics that is included in the Y-chromosomal haplotype reference database (YHRD, https://yhrd.org) and it is known as a rapidly mutating Y-STR. DYF387S1 is a multi-locus marker and the two paralogs are within a palindromic sequence which is a region prone to structural chromosome mutation. In this study, we investigated DYF387S1 copy number distribution and separately typed the two DYF387S1 paralogs in a Japanese population. We found different DYF387S1 copy numbers among haplogroups indicating that the differences had been caused by haplogroup-specific ancestral Y-chromosomal mutations, such as deletion, duplication and non-allelic gene conversion. In haplogroup C, it is likely that gene conversion between two DYF387S1 paralogs had occurred in the common ancestral Y-chromosome for paragroup C-M130* and duplication of DYF387S1 had occurred in the common ancestral Y-chromosome for haplogroup C-M131. Meanwhile, in haplogroup D, deletion of the upstream DYF387S1 paralog is likely to have occurred in the common ancestral Y-chromosome for paragroup D-M57* and duplication of the remaining DYF387S1 paralog is indicated in the common ancestral Y-chromosome for haplogroup D-M125. In haplogroup O, structural mutations changing the DYF387S1 copy number had probably not occurred in the common ancestral Y-chromosome. We also suggest that deletion of one DYF387S1 paralog occurred in haplogroup N and that deletion of one DYF387S1 paralog or DYF387S1 gene conversion occurred in haplogroup Q. This is the first study that has separately typed the two DYF387S1 paralogs in a large population dataset. As haplogroups C, D, N, O and Q are also observed in other populations, the ancestral mutation events indicated by this study may have affected DYF387S1 polymorphism in other areas of the world.

The Y-chromosome F haplogroup contributes to the development of Barrett's esophagus-associated esophageal adenocarcinoma in a white male population.

Barrett's esophagus (BE) is a metaplastic condition of the distal esophagus, resulting from longstanding gastroesophageal reflux disease (GERD). BE predisposes for the highly malignant esophageal adenocarcinoma (EAC). Both BE and EAC have the highest frequencies in white males. Only a subset of patients with GERD develop BE, while <0.5% of BE will progress to EAC. Therefore, it is most likely that the development of BE and EAC is associated with underlying genetic factors. We hypothesized that in white males, Y-chromosomal haplogroups are associated with BE and EAC. To investigate this we conducted a multicenter study studying the frequencies of the Y-chromosomal haplogroups in GERD, BE, and EAC patients. We used genomic analysis by polymerase chain reaction and restriction fragment length polymorphism to determine the frequency of six Y-chromosomal haplogroups (DE, F(xJ,xK), K(xP), J, P(xR1a), and R1a) between GERD, BE, and EAC in a cohort of 1,365 white males, including 612 GERD, 753 BE patients, while 178 of the BE patients also had BE-associated EAC. Univariate logistic regression analysis was used to compare the outcomes. In this study, we found the R1a (6% vs. 9%, P = 0.04) and K (3% vs. 6%, P = 0.035) to be significantly underrepresented in BE patients as compared to GERD patients with an odds ratio (OR) of 0.63 (95% CI 0.42-0.95, P = 0.03) and of 0.56 (95% CI 0.33-0.96, P = 0.03), respectively, while the K haplogroup was protective against EAC (OR 0.30; 95% CI 0.07-0.86, P = 0.05). A significant overrepresentation of the F haplogroup was found in EAC compared to BE and GERD patients (34% vs. 27% and 23%, respectively). The F haplogroup was found to be a risk factor for EAC with an OR of 1.5 (95% CI 1.03-2.19, P = 0.03). We identified the R1a and K haplogroups as protective factors against development of BE. These haplogroups have low frequencies in white male populations. Of importance is that we could link the presence of the predominantly occurring F haplogroup in white males to EAC. It is possible that this F haplogroup is associated to genetic variants that predispose for the EAC development. In future, the haplogroups could be applied to improve stratification of BE and GERD patients with increased risk to develop BE and/or EAC.

Polymorphisms and microvariant sequences in the Japanese population for 25 Y-STR markers and their relationships to Y-chromosome haplogroups.

Y-chromosomal short tandem repeat (Y-STR) markers have been used for forensic purposes such as kinship analysis of male-linage and detection of a male DNA component in a mixture of male and female DNA. Recently, rapidly mutating Y-STR (RM Y-STR) markers were reported that are expected to help distinguish close male relatives. This study provides data of Y-chromosomal haplotypes for 25 Y-STR markers, including six RM Y-STR markers (DYS576, DYS627, DYS518, DYS570, DYS449 and DYF387S1) typed with the Yfiler™ Plus kit in 1299 males of the Japanese population. Discrimination capacity increased from 87.2% for 16 Y-STR markers with the Yfiler™ kit to 99.6% for 25 Y-STR markers with the Yfiler™ Plus kit. We characterized sequences of observed microvariant alleles of eight Y-STR markers and a low-amplified allele of DYS390 by Sanger sequencing. DYF387S1, a multi-locus Y-STR marker that is located at two positions on the human Y-chromosome, was observed in tri-allelic patterns in 51 of 1299 samples (3.9%) and we found an extremely high frequency of the tri-allelic pattern of DYF387S1 in haplogroup C-M131. We also analyzed Y-STR gene diversity in each haplogroup and its relevance to mutation rates.

The Eastern side of the Westernmost Europeans: Insights from subclades within Y-chromosome haplogroup J-M304.

OBJECTIVES: We examined internal lineages and haplotype diversity in Portuguese samples belonging to J-M304 to improve the spatial and temporal understanding of the introduction of this haplogroup in Iberia, using the available knowledge about the phylogeography of its main branches, J1-M267 and J2-M172. METHODS: A total of 110 males of Portuguese descent were analyzed for 17 Y-chromosome bi-allelic markers and seven Y-chromosome short tandem repeats (Y-STR) loci. RESULTS: Among J1-M267 individuals (n = 36), five different sub-haplogroups were identified, with the most common being J1a2b2-L147.1 (∼72%), which encompassed the majority of representatives of the J1a2b-P58 subclade. One sample belonged to the rare J1a1-M365.1 lineage and presented a core Y-STR haplotype consistent with the Iberian settlement during the fifth century by the Alans, a people of Iranian heritage. The analysis of J2-M172 Portuguese males (n = 74) enabled the detection of the two main subclades at very dissimilar frequencies, J2a-M410 (∼80%) and J2b-M12 (∼20%), among which the most common branches were J2a1(xJ2a1b,h)-L26 (22.9%), J2a1b(xJ2a1b1)-M67 (20.3%), J2a1h-L24 (27%), and J2b2-M241 (20.3%). CONCLUSIONS: While previous inferences based on modern haplogroup J Y-chromosomes implicated a main Neolithic dissemination, here we propose a later arrival of J lineages into Iberia using a combination of novel Portuguese Y-chromosomal data and recent evidence from ancient DNA. Our analysis suggests that a substantial tranche of J1-M267 lineages was likely carried into the Iberian Peninsula as a consequence of the trans-Mediterranean contacts during the first millennium BC, while most of the J2-M172 lineages may be associated with post-Neolithic population movements within Europe.

Interaction between Y chromosome haplogroup O3* and 4-n-octylphenol exposure reduces the susceptibility to spermatogenic impairment in Han Chinese.

Certain genetic background (mainly Y chromosome haplogroups, Y-hg) may modify the susceptibility of certain environmental exposure to some diseases. Compared with respective main effects of genetic background or environmental exposure, interactions between them reflect more realistic combined effects on the susceptibility to a disease. To identify the interactions on spermatogenic impairment, we performed Y chromosome haplotyping and measurement of 9 urinary phenols concentrations in 774 infertile males and 520 healthy controls in a Han Chinese population, and likelihood ratio tests were used to examine the interactions between Y-hgs and phenols. Originally, we observed that Y-hg C and Y-hg F* might modify the susceptibility to male infertility with urinary 4-n-octylphenol (4-n-OP) level (Pinter = 0.005 and 0.019, respectively). Subsequently, based on our results, two panels were tested to identify the possible protective sub-branches of Y-hg F* to 4-n-OP exposure, and Y-hg O3* was uncovered to interact with 4-n-OP (Pinter = 0.019). In conclusion, while 4-n-OP shows an adverse effect on spermatogenesis, Y-hg O3* makes individuals more adaptive to such an effect for maintaining basic reproductive capacity.

Copy number variation of functional RBMY1 is associated with sperm motility: an azoospermia factor-linked candidate for asthenozoospermia.

STUDY QUESTION: What is the influence of copy number variation (CNV) in functional RNA binding motif protein Y-linked family 1 (RBMY1) on spermatogenic phenotypes? SUMMARY ANSWER: The RBMY1 functional copy dosage is positively correlated with sperm motility, and dosage insufficiency is an independent risk factor for asthenozoospermia. WHAT IS KNOWN ALREADY: RBMY1, a multi-copy gene expressed exclusively in the adult testis, is one of the most important candidates for male infertility in the azoospermia factor (AZF) region of the Y-chromosome. RBMY1 encodes an RNA-binding protein that serves as a pre-mRNA splicing regulator during spermatogenesis, and male mice deficient in Rbmy are sterile. STUDY DESIGN, SIZE, DURATION: A total of 3127 adult males were recruited from 2009 to 2016; of this group, the dosage of RBMY1 functional copy were investigated in 486 fertile males. In the remaining 2641 males with known spermatogenesis status, 1070 Y-chromosome haplogroup (Y-hg) O3* or O3e carriers without chromosomal aberration or known AZF structure mutations responsible for spermatogenic impairment, including 506 men with normozoospermia and 564 men with oligozoospermia or/and asthenozoospermia, were screened, and the RBMY1 functional copy dosage and copy conversion were determined to explore their associations with sperm phenotypes. The correlation between RBMY1 dosage and its mRNA level or RBMY1 protein level and the correlation between sperm RBMY1 level and motility were analysed in 15 testis tissue samples and eight semen samples. Ten additional semen samples were used to confirm the subcellular localization of RBMY1 in individual sperm. PARTICIPANTS/MATERIALS, SETTING, METHODS: All the Han volunteers donating whole blood, semen and testis tissue were from southwest China. RBMY1 copy number, copy conversion, mRNA/protein amount and protein location in sperm were detected using the AccuCopy® assay method, paralog ratio test, quantitative PCR, western blotting and immunofluorescence staining methods, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: This study identified Y-hg-independent CNV of functional RBMY1 in the enrolled population. A difference in the distribution of RBMY1 copy number was observed between the group with normal sperm motility and the group with asthenozoospermia. A positive correlation between the RBMY1 copy dosage and sperm motility was identified, and the males with fewer than six copies of RBMY1 showed an elevated risk for asthenozoospermia relative to those with six RBMY1 copies, the most common dosage in the population. The RBMY1 copy dosage was positively correlated with its mRNA and protein level in the testis. Sperm with high motility were found to carry more RBMY1 protein than those with relatively low motility. The RBMY1 protein was confirmed to predominantly localize in the neck and mid-piece region of sperm as well as the principal piece of the sperm tail. Our population study completes a chain of evidence suggesting that RBMY1 influences the susceptibility of males to asthenozoospermia by modulating sperm motility. LIMITATIONS REASONS FOR CAUTION: High sequence similarity between the RBMY1 functional copies and a large number of pseudogenes potentially reduces the accuracy of the copy number detection. The mechanism underlying the CNV in RBMY1 is still unclear, and the effect of the structural variations in the RBMY1 copy cluster on the copy dosage of other protein-coding genes located in the region cannot be excluded, which may potentially bias our observations. WIDER IMPLICATIONS OF THE FINDINGS: Asthenozoospermia is a multi-factor complex disease with a limited number of proven susceptibility genes. This study identified a novel genomic candidate independently contributing to the condition, enriching our understanding of the role of AZF-linked genes in male reproduction. Our finding provides insight into the physiological and pathological characteristics of RBMY1 in terms of sperm motility, supplies persuasive evidence of the significance of RBMY1 copy number analysis in the clinical counselling of male infertility resulting from asthenozoospermia. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by the National Natural Science Foundation of China (Nos. 81370748 and 30971598). The authors have no conflicts of interest.

Y chromosome haplogroup D2a1 is significantly associated with high levels of luteinizing hormone in Japanese men.

The association between the Y chromosome haplogroup D2 and risk of azoospermia and low sperm motility has been previously studied, and it was indicated that haplogroups DE (YAP lineage) are associated with prostate cancer risk in Japanese males. Our assumption had been that Y chromosome haplogroups may be associated with sex hormone levels, because sex hormones have been deemed responsible for spermatogenesis and carcinogenesis. In this study, we assessed the association between Y chromosome haplogroups and sex hormone levels, including those of testosterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), luteinizing hormone (LH), inhibin-B, and calculated free testosterone (cFT), in 901 young men from the general Japanese population (cohort 1) and 786 Japanese men of proven fertility (cohort 2). We found that the haplogroup D2a1 was significantly associated with high LH levels in a combined analysis involving two cohorts (ß = 0.068, SE = 0.025, p = 0.0075), following correction for multiple testing. To date, this result is the first evidence that implicates Y chromosome haplogroups in an association with sex hormone levels.

Gene copy number alterations in the azoospermia-associated AZFc region and their effect on spermatogenic impairment.

The azoospermia factor c (AZFc) region in the long arm of human Y chromosome is characterized by massive palindromes. It harbors eight multi-copy gene families that are expressed exclusively or predominantly in testis. To assess systematically the role of the AZFc region and these eight gene families in spermatogenesis, we conducted a comprehensive molecular analysis (including Y chromosome haplogrouping, AZFc deletion typing and gene copy quantification) in 654 idiopathic infertile men and 781 healthy controls in a Han Chinese population. The b2/b3 partial deletion (including both deletion-only and deletion-duplication) was consistently associated with spermatogenic impairment. In the subjects without partial AZFc deletions, a notable finding was that the frequency of DAZ and/or BPY2 copy number alterations in the infertile group was significantly higher than in the controls. Combined patterns of DAZ and/or BPY2 copy number abnormality were associated with spermatogenic impairment when compared with the pattern of all AZFc genes with common level copies. In addition, in Y chromosome haplogroup O1 (Y-hg O1), the frequency of copy number alterations of all eight gene families was significantly higher in the case group than that in the control group. Our findings indicate that the DAZ, BPY2 genes may be prominent players in spermatogenesis, and genomic rearrangements may be enriched in individuals belonging to Y-hg O1. Our findings emphasize the necessity of routine molecular analysis of AZFc structural variation during the workup of azoospermia and/or oligozoospermia, which may diminish the genetic risk of assisted reproduction.

DAZ duplications confer the predisposition of Y chromosome haplogroup K* to non-obstructive azoospermia in Han Chinese populations.

STUDY QUESTION: What are the genetic causes for the predisposition of certain Y chromosome haplogroups (Y-hgs) to spermatogenic impairment? SUMMARY ANSWER: The AZFc(azoospermia factor c)/DAZ (deleted in azoospermia) duplications might underlie the susceptibility of Y-hg K* to spermatogenic impairment. WHAT IS KNOWN ALREADY: The roles of Y chromosomal genetic background in spermatogenesis are controversial and vary among human populations. Individuals in predisposed Y-hgs may carry some genetic factors, which might be a potential genetic modifier for the Y-hg-specific susceptibility to spermatogenic impairment. STUDY DESIGN, SIZE, DURATION: A total of 2444 individuals with azoospermia or oligozoospermia and 2456 healthy controls were recruited to this study from March 2004 and January 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a two-stage association study to investigate the risk and/or protective Y-hgs for spermatogenic impairment. In addition, the genetic causes for the predisposition of certain Y-hg to spermatogenic impairment were investigated. Deletion typing and DAZ gene copy number quantification were performed for individuals in predisposed Y-hgs. MAIN RESULTS AND THE ROLE OF CHANCE: Y-hgs K* and O3e* showed significantly different distribution between cases and controls consistently in two-stage studies. Combined analyses identified significant predisposition to non-obstructive azoospermia in Y-hg K* [odds ratio (OR) 8.58; 95% confidence interval (CI) 3.31-22.28; P = 1.40 × 10⁻5], but a protecting effect in Y-hg O3e* (OR 0.64; 95% CI 0.53-0.78; P = 4.20 × 10⁻5). Based on the dynamic nature of the Y chromosome, we hypothesized that Y-hgs K* and O3e* may be accompanied by modifying genetic factors for their predisposing or protecting effects in spermatogenesis. Accordingly, we quantified the multi-copy DAZ gene, which has variable copy numbers between individuals and plays an important role in spermatogenesis. In combined analysis, we found that the over-dosage of DAZ was significantly more frequent in Y-hg K* than in O3e* (OR 4.79; 95% CI 1.67-13.70; P = 6 × 10⁻³). LIMITATIONS, REASONS FOR CAUTION: Owing to the inconsistency of genetic background, it remains to be determined whether the results derived from Han Chinese populations are applicable to other ethnic groups. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study can advance the etiology of spermatogenic impairment, and also shed new light on Y chromosome evolution in human populations. Y-hg-specific genetic factors of modifying spermatogenic phenotypes deserve further investigation in larger and diverse populations.