Uniparental Genetic Heritage of Belarusians: Encounter of Rare Middle Eastern Matrilineages with a Central European Mitochondrial DNA Pool

Ethnic Belarusians make up more than 80% of the nine and half million people inhabiting the Republic of Belarus. Belarusians together with Ukrainians and Russians represent the East Slavic linguistic group, largest both in numbers and territory, inhabiting East Europe alongside Baltic-, Finno-Permic- and Turkic-speaking people. Till date, only a limited number of low resolution genetic studies have been performed on this population. Therefore, with the phylogeographic analysis of 565 Y-chromosomes and 267 mitochondrial DNAs from six well covered geographic sub-regions of Belarus we strove to complement the existing genetic profile of eastern Europeans. Our results reveal that around 80% of the paternal Belarusian gene pool is composed of R1a, I2a and N1c Y-chromosome haplogroups – a profile which is very similar to the two other eastern European populations – Ukrainians and Russians. The maternal Belarusian gene pool encompasses a full range of West Eurasian haplogroups and agrees well with the genetic structure of central-east European populations. Our data attest that latitudinal gradients characterize the variation of the uniparentally transmitted gene pools of modern Belarusians. In particular, the Y-chromosome reflects movements of people in central-east Europe, starting probably as early as the beginning of the Holocene. Furthermore, the matrilineal legacy of Belarusians retains two rare mitochondrial DNA haplogroups, N1a3 and N3, whose phylogeographies were explored in detail after de novo sequencing of 20 and 13 complete mitogenomes, respectively, from all over Eurasia. Our phylogeographic analyses reveal that two mitochondrial DNA lineages, N3 and N1a3, both of Middle Eastern origin, might mark distinct events of matrilineal gene flow to Europe: during the mid-Holocene period and around the Pleistocene-Holocene transition, respectively

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis

Identification of alterations in the nucleotide sequence of the chromatin remodeling gene PBRM1 in clear cell renal cell carcinoma patients

Kidney cancer is a heterogeneous group of malignant tumors, the vast majority of which are renal cell carcinomas (RCC) of various morphological types, of which the most common is the clear cell renal cell carcinoma (ccRCC). Particular attention in the carcinogenesis of the ccRCC is given to a number of tumor suppressor genes located on the short arm of the third chromosome. One of these genes, which are inactivated in the case of ccRCC is the PBRM1 gene encoding the PBAF SWI/SNF subunit of the chromatin remodeling complex, BAF180. The PBRM1 gene is located on the short arm of the third chromosome in the 3p21 region near the von Hippel-Lindau gene (VHL), the mutation in which is the main event in the occurrence of ccRCC. The aim of our investigation is identification of changes in the nucleotide sequence of the PBRM1 tumor suppressor gene in patients with ccRCC. 210 pairs of DNA samples isolated from ccRCC tissue were studied. Analysis of changes in the nucleotide sequence of DNA was carried out by HRM analysis and direct sequencing. In the PBRM1 gene, two somatic mutations were found (c.233G>A (p.D45N) in exon 2, c.1675-1676delTC in exon 15) which were not described previously, and one known polymorphic variant rs17264436 (in exon 23). The frequency of detected mutations was 0.95 % of cases. Analysis of the allelic association for the polymorphic locus rs17264436 showed a statistically significant increase in the risk of developing advanced kidney cancer in carriers of allele rs17264436*A, which can be used in the development of prognostic marker panels. Perhaps the low frequency of mutations in the samples we studied is due to the fact that the inactivation of the PBRM1 gene takes place in other ways, and may also be due to the ethno-specificity of the studied group of patients

Нейрофиброматоз 1‑го типа: результаты собственного исследования (Республика Башкортостан)

Introduction. Neurofibromatosis type 1 (NF1) is the most common hereditary tumor syndrome (frequency of its occurrence in the world is 1 : 3000 of the population). The main clinical manifestations of the disease are multiple café-au-lait macules on the skin and neurofibromas, skeletal abnormalities and cognitive deficits. The disease is based on mutations in the oncosuppressor gene NF1. This disease is characterized by significant clinical polymorphism of manifestations, even among members of the same family. No geno-phenotypic correlations were found for NF1. Therefore, it is assumed that modifier genes are the cause of the varying expressiveness of the disease. Materials and methods. Clinical-epidemiological and molecular-genetic research of patients with NF1 in the Republic of Bashkortostan (RB) was carried out. Sequencing was used to search for intragenic mutations in 57 exons of the NF1 gene. Microsatellite analysis was used to detect the deletion of the entire gene.Results. The frequency of occurrence of NF1 in RB was 1 : 10153 of the population. Analysis of the clinical manifestations of NF1 in RB patients showed a lower incidence of brain cysts in patients born in mixed marriages, which indicates the protective role of mestization. In patients with NF1 who inherited the disease from the mother, a more frequent development of skeletal anomalies and facial dysmorphism was determined. We identified 1 deletion of the entire NF1 gene in 1 patient and 14 intragenic mutations (c.205-1G>C, с.1278G>A, c.1369_1370insGGGTC, с.1570G>A, с.1973_1974delTC, c.2806A>T, с.2991-1G>C, c.3158C>G, с.3526_3528delAGA, с.3826delC, с.4514+5G>A, с.4537С>Т, c.5758_5761delTTGA, с.6792С>A) in 20 patients with NF1. We determined the random distribution of the types of mutations and did not reveal the specific features of the NF1 clinic depending on the type of mutations.Conclusions. The protective role of crossbreeding in relation to brain cysts, as well as the predominance of skeletal anomalies in patients with NF1 inheritance from the mother, indicate the role of modifier genes in the pathogenesis of the disease. The identified mutations in the NF1 gene will allow us to perform prenatal prevention of NF1 in RB patients.Введение. Нейрофиброматоз 1-го типа (НФ1) – самый распространенный наследственный опухолевый синдром (частота встречаемости в мире – 1 : 3000 населения). Основными клиническими проявлениями болезни являются множественные пигментные пятна на коже и нейрофибромы, скелетные аномалии и когнитивный дефицит. В основе болезни лежат мутации в онкосупрессорном гене NF1. Характерен выраженный клинический полиморфизм НФ1 даже среди членов одной семьи, гено-фенотипических корреляций не выявлено. В связи с этим предполагается, что гены-модификаторы влияют на патогенез варьирующей экспрессивности болезни.Материалы и методы. Проведено клинико-эпидемиологическое и молекулярно-генетическое исследование больных НФ1 в Республике Башкортостан (РБ). Поиск внутригенных мутаций осуществлялся методом секвенирования 57 экзонов гена NF1, делеции всего гена – с использованием микросателлитного анализа. Результаты. Частота встречаемости НФ1 в РБ составила 1 : 10153 населения. Анализ клинических проявлений НФ1 у больных из РБ показал меньшую частоту встречаемости кист головного мозга у больных, рожденных в смешанном браке, что свидетельствует о протективной роли метисации. При наследовании НФ1 от матери определено более частое развитие скелетных аномалий и дизморфизма лица. Выявлены 1 делеция всего гена NF1 у 1 пациента и 14 внутригенных мутаций у 20 больных НФ1 (c.205-1G>C, с.1278G>A, c.1369_1370insGGGTC, с.1570G>A, с.1973_1974delTC, c.2806A>T, с.2991-1G>C, c.3158C>G, с.3526_3528delAGA, с.3826delC, с.4514+5G>A, с.4537С>Т, c.5758_5761delTTGA, с.6792С>A). Показано случайное распределение типов мутаций, не выявлено специфических особенностей клиники НФ1 в зависимости от типа мутаций.Выводы. Протективная роль метисации в отношении кист головного мозга, а также преобладание скелетных аномалий при наследовании НФ1 от матери свидетельствуют о роли генов-модификаторов в патогенезе болезни. Идентификация мутаций в гене NF1 позволит проводить пренатальную профилактику НФ1 у населения РБ

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

To date, most BC GWASs have been performed Background Polygenic risk score (PRS), calculated in individuals of European (EUR) ancestry, and based on genome-wide association studies (GWASs), the generalisation of EUR-based PRS to other can improve breast cancer (BC) risk assessment. populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. Methods We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. Results In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). Conclusions Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.</p

The Western and Eastern Roots of the Saami - The Story of Genetic "Outliers" Told by Mitochondrial DNA and Y Chromosomes

Funding Information: We thank Tatyana Karafet and Boris Malyarchuk, for useful information; Henry Harpending, for the program POPSTR; Vincent Macaulay, for the program SAMPLING; Ille Hilpus and Jaan Lind, for technical assistance; and Charles Kurland and Thomas Gilbert, for helpful discussion and comments. We are grateful to two anonymous reviewers for their suggestions and advice. The research of R.V. was supported by Estonian basic research grant 514 and European Commission Directorate General Research grant ICA1CT20070006. The research of T.K. was supported by Estonian basic research grant 5574. The work of E.K. was supported by the Russian Foundation for Basic Research (project number 01-04-48487a) and the Ministry of Sciences and Technology of Russia. M.G., S.Z., and L.O. received support from expedition grants from the Siberian Branch of the Russian Academy of Sciences (1992–1997) and the Russian Foundation of Basic Research (project number 02-06-80524-a), and the research of P.R. received support from project number 0196005 of the Ministry of Science and Technology of the Republic of Croatia.The Saami are regarded as extreme genetic outliers among European populations. In this study, a high-resolution phylogenetic analysis of Saami genetic heritage was undertaken in a comprehensive context, through use of maternally inherited mitochondrial DNA (mtDNA) and paternally inherited Y-chromosomal variation. DNA variants present in the Saami were compared with those found in Europe and Siberia, through use of both new and previously published data from 445 Saami and 17,096 western Eurasian and Siberian mtDNA samples, as well as 127 Saami and 2,840 western Eurasian and Siberian Y-chromosome samples. It was shown that the "Saami motif" variant of mtDNA haplogroup U5b is present in a large area outside Scandinavia. A detailed phylogeographic analysis of one of the predominant Saami mtDNA haplogroups, U5b1b, which also includes the lineages of the "Saami motif," was undertaken in 31 populations. The results indicate that the origin of U5b1b, as for the other predominant Saami haplogroup, V, is most likely in western, rather than eastern, Europe. Furthermore, an additional haplogroup (H1) spread among the Saami was virtually absent in 781 Samoyed and Ob-Ugric Siberians but was present in western and central European populations. The Y-chromosomal variety in the Saami is also consistent with their European ancestry. It suggests that the large genetic separation of the Saami from other Europeans is best explained by assuming that the Saami are descendants of a narrow, distinctive subset of Europeans. In particular, no evidence of a significant directional gene flow from extant aboriginal Siberian populations into the haploid gene pools of the Saami was found.Peer reviewe

Breast cancer risks associated with missense variants in breast cancer susceptibility genes

BACKGROUND: Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. METHODS: We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. RESULTS: The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. CONCLUSIONS: These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility