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Post by Admin on Apr 23, 2022 17:33:02 GMT
Diagnostics Original Article Catalogue of inherited disorders found among the Irish Traveller population Abstract Background Irish Travellers are an endogamous, nomadic, ethnic minority population mostly resident on the island of Ireland with smaller populations in Europe and the USA. High levels of consanguinity result in many rare autosomal recessive disorders. Due to founder effects and endogamy, most recessive disorders are caused by specific homozygous mutations unique to this population. Key clinicians and scientists with experience in managing rare disorders seen in this population have developed a de facto advisory service on differential diagnoses to consider when faced with specific clinical scenarios. Objective(s) To catalogue all known inherited disorders found in the Irish Traveller population. Methods We performed detailed literature and database searches to identify relevant publications and the disease mutations of known genetic disorders found in Irish Travellers. Results We identified 104 genetic disorders: 90 inherited in an autosomal recessive manner; 13 autosomal dominant and one a recurring chromosomal duplication. Conclusion We have collated our experience of inherited disorders found in the Irish Traveller population to make it publically available through this publication to facilitate a targeted genetic approach to diagnostics in this ethnic group. dx.doi.org/10.1136/jmedgenet-2017-104974Irish Travellers are an endogamous, ethnically Irish population numbering approximately 40,000 within the island of Ireland with up to 10,000 living on mainland Europe. Irish Travellers practice cousin marriage and we recognise > 90 autosomal recessive disorders that occur within their population. The majority of autosomal recessive disorders are due to homozygous mutations. Certain disorders cluster within certain clans and there are geographical differences in incidence of disorders depending where they come from in Ireland. There is expertise within our group on the disorders common within this population which could help with diagnosis in children and adults presenting to centres where the expertise does not exist. Top diagnoses in Metabolics: Galactosemia Hurler Syndrome I cell disease Hyperprolinaemia Infantile liver failure type 1 ILFS1 Glutaric aciduria type 1 Glycogen storage disorder (GSD) types III and V Classical PKU and pterin defects Methylmalonic aciduria Leigh disease and Respiratory Chain Disorders Sly syndrome Top diagnoses in Clinical Genetics Osteogenesis Imperfecta (lepre1 gene) Natural Killer Cell and Glucocorticoid deficiency with DNA repair defect NKGCD Primary ciliary dyskinesia (Genetic Heterogeneity) McArdles Microcephaly Fanconia’s anaemia (Genetic Heterogeneity) Walker-Warburg Merosin negative myopathy Multiple epiphyseal dysplasia Cardiomyopathy Deafness Cohen syndrome Lebers amaurosis (Genetic Heterogeneity) Top diagnoses in neurology Epilepsy Friedreich’s Ataxia I cell disease Leigh disease GSD V Microcephaly Walker-Warburg Merosin negative myopathy Lebers amaurosis Cohen syndrome Top diagnosis in endocrinology Natural Killer Cell and Glucocorticoid deficiency with DNA repair defect NKGCD Congenital adrenal hyperplasia 46,XY female phenotype (Genetic Heterogeneity) Osteogenesis imperfecta Familial Hyperinsulinism (Genetic Heterogeneity) Wolcott-Rallison
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Post by Admin on Apr 23, 2022 18:35:43 GMT
PEOPLE with at least two grandparents from the Traveller community are being asked to take part in a new genetic study. The research will provide a unique opportunity to understand how Scottish Travellers relate to Irish Travellers, English Gypsies and Welsh Kale, as well as their settled neighbours. Some 400 people are being invited to join the study, which will also shed light on any genetic risk factors for health. Representatives of the community asked researchers at Edinburgh University to carry out the study, as there has been no genetic research involving Scottish Travellers. The study will build upon previous work by the Edinburgh team with the Irish Traveller community, which helped them gain official recognition as a distinct ethnic minority. Participants will complete an online questionnaire about their health and lifestyle. They will also be asked to return a saliva sample by post, which will be used for DNA analysis. Lead researcher, Professor Jim Wilson, said: “Scottish Traveller groups have never been involved in studies using the power of modern genetics. “I was delighted to be asked by representatives of this community to carry out a study that will reveal how the Traveller communities fit into the genetic landscape of Scotland and the British Isles.” Samantha Donaldson, a Scottish Traveller from Dunfermline and member of the study’s public involvement panel, said the findings could be useful in proving or disproving origin myths about the Travellers. She added: “Travellers have some of the greatest health inequalities in Scotland. If we are genetically predisposed to certain conditions more than other groups, or if we have illnesses that are more likely to affect us, then health professionals may be able to use data to address some of these inequalities.”
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Post by Admin on Apr 24, 2022 17:12:30 GMT
Origins, admixture and founder lineages in European Roma Begoña Martínez-Cruz, Isabel Mendizabal, Christine Harmant, Rosario de Pablo, Mihai Ioana, Dora Angelicheva, Anastasia Kouvatsi, Halyna Makukh, Mihai G Netea, Horolma Pamjav, Andrea Zalán, Ivailo Tournev, Elena Marushiakova, Vesselin Popov, Jaume Bertranpetit, Luba Kalaydjieva, Lluis Quintana-Murci & David Comas on behalf of and the Genographic Consortium
Abstract The Roma, also known as ‘Gypsies’, represent the largest and the most widespread ethnic minority of Europe. There is increasing evidence, based on linguistic, anthropological and genetic data, to suggest that they originated from the Indian subcontinent, with subsequent bottlenecks and undetermined gene flow from/to hosting populations during their diaspora. Further support comes from the presence of Indian uniparentally inherited lineages, such as mitochondrial DNA M and Y-chromosome H haplogroups, in a significant number of Roma individuals. However, the limited resolution of most genetic studies so far, together with the restriction of the samples used, have prevented the detection of other non-Indian founder lineages that might have been present in the proto-Roma population. We performed a high-resolution study of the uniparental genomes of 753 Roma and 984 non-Roma hosting European individuals. Roma groups show lower genetic diversity and high heterogeneity compared with non-Roma samples as a result of lower effective population size and extensive drift, consistent with a series of bottlenecks during their diaspora. We found a set of founder lineages, present in the Roma and virtually absent in the non-Roma, for the maternal (H7, J1b3, J1c1, M18, M35b, M5a1, U3, and X2d) and paternal (I-P259, J-M92, and J-M67) genomes. This lineage classification allows us to identify extensive gene flow from non-Roma to Roma groups, whereas the opposite pattern, although not negligible, is substantially lower (up to 6.3%). Finally, the exact haplotype matching analysis of both uniparental lineages consistently points to a Northwestern origin of the proto-Roma population within the Indian subcontinent.
Introduction The Roma constitute one of the less documented human diaspora phenomena and an excellent model to evaluate the consequences of recent, multiple, and widespread dispersals and founder events. Social and political factors preclude the collection of precise census on the Roma, but they are acknowledged as the largest ethnic minority of Europe, with a population of up to 10 million people spread across the continent and mostly concentrated in Central and South-Eastern Europe.1, 2
Based on linguistic, cultural, anthropological, and genetic evidence, the proto-Roma population is thought to have originated on the Indian subcontinent.1, 3, 4, 5, 6, 7, 8, 9 Their migration routes probably encompassed Persia, Armenia, and the Balkans, with a large consensus on their arrival in Eastern Europe around a thousand years ago. Within a period of about two centuries, most Roma became sedentary in the Balkan Peninsula (Balkan Roma), in the relatively ethnically tolerant surroundings of the newly established Ottoman Empire.10 Some groups instead initiated a rapid migration that, by the end of the fifteenth century, had spread all across the European continent.1 Some, whose descendants are now known as Vlax Roma, moved across the Danube into the Danubian Principalities (nowadays Romania, Moldova, and parts of Hungary) where they were forced into slavery and divided into small groups. Another migration group out of the Balkan Peninsula, known as the Romungro, spread within the Austro-Hungarian Empire, where they were subject to attempts at assimilation.11 Other Roma groups continued moving in small groups into Central and Western Europe, where they were persecuted during Medieval times.1, 2 The abolition of Roma slavery in the Danubian Principalities Walachia and Moldova in the nineteenth century was followed by a mass migration, spreading the Vlax Roma into nearby countries and worldwide; most kept their endogamous rules and nomadic lifestyle.1, 3, 12 Recent Roma movements include migrations during the twentieth century triggered by the economic and political transformation of Eastern Europe.13
From a medical perspective, the genetic drift due to multiple founder events and endogamy in the Roma have increased the prevalence of Mendelian disorders caused by variants that are rare in other populations.14, 15 This complex demographic pattern might have also caused an increase of slightly deleterious variants in Roma groups as a result of a lower efficiency of purifying selection in purging deleterious alleles.16
The east-to-west genetic gradient observed in Roma populations is compatible with the postulated waves of migration within Europe.4, 7, 17, 18 All European Roma appear to descend from a low number of founders, and to have diverged into socially distinct endogamous groups after their arrival in Europe.14, 17, 18 The Indian component of the proto-Roma ancestry was supported by the identification of disease-causing mutations described in affected subjects in India and Pakistan.9, 15, 19, 20 Furthermore, the Roma show high frequencies of the H-M69 Y-chromosome4, 17, 21, 22 and mitochondrial DNA (mtDNA) M5, M18, M25, and M35 haplogroups4, 7, 17, 23, 24, 25 reported to have an Indian origin.25, 26, 27 Accordingly, studies of autosomal markers identified the Northwest of India as the most probable homeland of the European Roma.6
Despite these previous genetic studies, the Roma demographic history remains poorly understood. Y-chromosome and mtDNA lineages other than H and the M major haplogroups, respectively, have been attributed to genetic influences from populations along the proto-Roma migration way7, 21 without a more specific definition of their geographic origins. Furthermore, the small numbers and different sets of Y-STRs used in some studies, the insufficient and variable phylogenetic resolution, and the local character of the studies have prevented the reconstruction of a clear general picture.4, 22, 28, 29, 30 Moreover, studies that used a large number of markers were forced to reduce the phylogenetic resolution in order to compare with previous data.21 In addition to these limitations, the information of the Roma volunteers has been restricted to their geography tracks (ie, country of the sampling) ignoring the Roma group affiliation, which might have masked their complex population history.
To overcome these limitations, we analyzed uniparental lineages at high resolution in ~750 European Roma and ~980 non-Roma, in order to: (1) test whether there is a paternal and a maternal signature of the spread of Roma throughout Europe from the Balkan Peninsula; (2) revisit the potential role of geography and migration routes in the genetic structure of Roma; (3) determine the degree of gene flow from hosting populations to Roma and vice versa, and whether this gene flow is sex-biased; and (4) investigate the origins of the Roma ancestors within the Indian subcontinent.
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Post by Admin on Apr 24, 2022 19:23:16 GMT
Materials and methods Sample collection One thousand seven hundred and thirty-seven unrelated individuals self-identified as Roma (N=753) or non-Roma (N=984) were collected after the corresponding ethical approval and informed consent (Table 1). Greek Roma samples were collected in the villages of Hraklia, Nigrita, Dendropotamos, Xanthi, Volos, Sofades, and Ahaia. Greek hosts were collected from several locations in continental Greece, avoiding big cities. The Bulgarian Roma samples are a sub-sample of those in Morar et al9 and Gresham et al,17 including several Roma groups (Supplementary Table S4) that fall into two broader categories: Balkan and Vlax (Table 1). The Balkan category included the initial settlers in Bulgaria, whereas the Vlax Roma represent groups that migrated to Bulgaria from Wallachia and Moldova. Their genotyping was extended for both Y-chromosome SNPs and STRs, and the mtDNA whole control region. Bulgarian host samples were those in Martinez-Cruz et al.31 Romanian Roma were Vlax Romani speakers sampled in several villages (Garla Mare, Lipovu, Goicea, Barca, and Sadova). Romanian general population was also sampled in the southwest region of the country. Hungarian Roma were those in Pamjav et al22 and Hungarian general population was from Volgyi et al.29 Hungarian Roma included mixed Hungarian Roma from all over the country. In addition, Romungro Roma from Taktaköz and Vlax Roma from Tiszavasvári and Tokaj in Eastern Hungary were also included.22 In the case of the Hungarian general population, no ethnic origin was recorded at sampling29 and, therefore, this sample may include up to 6%–8% Roma.22 The genotyping from the Hungarian samples was extended for both Y-chromosome SNPs and STRs, and the mtDNA whole control region. Slovak Roma samples are Romungro Roma collected in three villages (Moldava nad Bodvou, Jasov, and Medzev) in Eastern Slovakia. Slovak host population was sampled in several geographical areas of Slovakia. Ukrainian Romungro Roma were collected in three localities in the Zakarpattya region (Serednye, Antonivka, and Hudolovo) and Ukrainian hosts were sampled around Lviv.31 Spanish Roma samples were collected in Barcelona7 and Madrid, and they were Spanish speakers. The Spanish host population was obtained from the Spanish National DNA Bank.
Y-chromosome data One thousand seven hundred and thirty-two unrelated individuals from Roma (N=748) and host populations (N=984) were genotyped for 131 SNPs. A group of 121 SNPs were typed as in Martinez-Cruz et al,32 six SNPs were genotyped in a single multiplex (Multiplex-2),33 and four SNPs were typed with individual TaqMan assays (L48, M458, L2, and L20). Nomenclature of the haplogroups is in accordance with the Y-Chromosome Consortium.34 All individuals were typed for a set of 19 STRs: 17 using the Yfiler kit (Applied Biosystems, Foster City, CA, USA) and two STRs included in Multiplex-2 (Martinez-Cruz et al33 and Supplementary Table S2). Some individuals from previous studies using lower number of markers17, 22 were genotyped to the same resolution level. All individuals with complete genotypes were submitted to the Y-HRD database (accession numbers YA004094–YA004107). As the Yfiler kit amplifies DYS385a/b simultaneously, avoiding the determination of each of the two alleles (a or b), DYS385a/b were excluded from all analyses performed.
mtDNA data One thousand three hundred and forty-one samples from Roma (N=736) and host (N=605) populations were sequenced for both hypervariable segments (HVS) I and II of the control region (positions 16 001–573; Supplementary Table S3). In addition, 22 coding region SNPs were genotyped using the multiplex GenoCoRe22.35 For 12 samples (8 Spanish and 1 Slovakian Roma, and 3 Romanian non-Roma) only HVS-I could be sequenced. All complete sequences were submitted to EMPOP data base (under the accession number EMP00671). Mitochondrial haplogroup H was subtyped with a specific multiplex.33 Based on HVS and coding SNP data, individuals were assigned to mtDNA haplogroups using Haplogrep36 and the PhyloTree build 15.37 Owing to their phylogenetic uncertainty, indels at nucleotide positions 309, 315, and 16 193 were not taken into account.
Statistical analyses Haplogroup and haplotype diversities, mean number of pairwise differences, and haplotype frequencies were calculated with Arlequin 3.4.38 The potential role of geography and migration routes was tested through analyses of molecular variance (AMOVAs) by pooling populations into country or migration route (see Supplementary Table S4). Greek and some Hungarian Roma were not included in the AMOVA, owing to the lack of detailed information about their migrational group, and Ukrainian Roma were also excluded because of their low sample size. We used FST distances for the Y-STRs and number of pairwise differences for mtDNA sequence data.
We defined founder lineages as lineages that the Roma most probably incorporated before their spread across Europe.7 Besides those already defined in Mendizabal et al,7 we include as founder lineages those haplogroups common in Roma (with frequencies over 5%) and not present or rare (<2%) in other Europeans. This definition of founder lineages is conservative and the founder nature of the lineages was further explored by studying their internal diversity. Namely, WIMP values (weighted intralineage mean pairwise differences)39 were estimated for the Roma founding lineages. Given the lower resolution of the Y-chromosome compared with the mtDNA in the definition of founders, we also built phylogenetic networks that were computed through sequential reduced median and median joining using the NETWORK v.4610 software package40 and were weighted for intra-haplogroup variance. The STR DYS389II was excluded from network analyses, as indicated by the Network software authors.40 In order to quantify admixture, we counted the exact matches of lineages classified as Roma or non-Roma in origin (ie, founder versus non-founder), assuming that exact matches represent the minimum gene flow between populations.
Under a simple stepping stone model in which sub-populations diverge from the neighboring sub-population, one expects genetic drift to accumulate (intra-population diversity decreased and genetic distances increased) with time. We tested correlations between internal diversity through WIMP (and genetic distances through FST) and geography, taking as a proxy a geographical point related to the Roma migration routes (Plovdiv in Bulgaria for Balkan Roma, Sibiu in Romania for Vlax Roma, Mezökövesd in Hungary for Central Roma, and Zaragoza in Spain for Western Roma) and independently for founder and non-founder lineages.
We constructed a Bayesian skyline plot (BSP) for M mtDNA lineages using BEAST.41 MCMC samples were based on a run of 300 000 000 generations, sampled every 30 000, discarding the first 30 000 000 generations as burn-in. We used a constant linear function of population size change, the HKY substitution model with a gamma site heterogeneity model, and a strict clock with a mean substitution rate of 9.883E−8 substitutions/site/year.42 Results reported were based on three independent runs showing identical results, with values of effective sample sizes higher than 200 for the parameters of interest, and after the visual evaluation of the convergence of the chains in stationary distributions by using the software Tracer v.1.6.43
Indian geographic areas were tested as putative origins for Roma lineages. We used a database with a total of 641 Indian Y-chromosomes from five regions,44 excluding the Northeastern populations, of Tibeto-Burman origin, and searched for identical matches of H-M52 Roma haplotypes. Identical matches for the mtDNA M lineages were assessed by comparison with the Indian database45 as in Medizabal et al.46 The weighted proportion of Roma lineages was used to infer the probabilities of origin.
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Post by Admin on Apr 25, 2022 17:08:37 GMT
Results Y-chromosome diversity and founder lineages Haplotype diversity was generally low for all Roma, notably for Bulgarian Vlax, Greek, Slovakian, Ukrainian, and Romanian samples (Supplementary Table S1). Conversely, most hosting populations displayed values of haplotype diversity higher than 99.9% for the same STRs markers, in agreement with the occurrence of founder effects among Roma groups.21 Details on haplogroup composition and haplogroup sharing are shown in Supplementary Figure S1 and Supplementary Table S2. Five paternal lineages were defined as founder in European Roma (Figure 1 and Supplementary Table S6). Up to 63% of Roma show a founder lineage, and from those 30% show founder non-H Indian lineages. More than 44% of the Roma individuals belonged to the Indian H-M52 haplogroup (including H-M82), ranging from 64% in the Balkan Peninsula to 21% in Spain (Supplementary Figure S1). In contrast, the frequency of haplogroup H was extremely low among non-Roma (1% in Bulgaria and 0.6% in Slovakia). It reached 5.3% in the non-Roma Hungarian population, although these individuals might actually be of Roma origin.22 Figure 1 (a) Y-chromosome and (b) mtDNA haplogroup frequencies corresponding to founder lineages in the European Roma populations. Non-founder haplogroups are grouped as ‘others’. WIMP values for the group of founder lineages are shown in brackets at the bottom of each population sample. In addition to H-M52 and its derivate H-M82 haplogroups, three non-Indian lineages (I-P259, J-M92, and J-M67) were defined as founders (Figure 1 and Supplementary Figure S1). I-P259 is present in all Roma groups (except in Spanish Roma) and absent in our non-Roma populations (with the exception of one Hungarian). The I-P259 network showed a star-like profile with reduced internal diversity (Supplementary Figure S2B). This suggests that the mutation might have appeared in the Roma population very recently and probably once, and spread due to drift. The founder lineages J-M92 and J-M67 are present in both Roma and hosts, as well as in the populations found in the Roma migration way out-of-India.47 Both lineages showed a star-like pattern in Roma with the exception of some individuals. Interestingly, the haplotypes within the star-like cluster were absent in the hosts, with the exception, again, of one Hungarian for J-M92 and one for J-M67 (Supplementary Figure S2). As these haplogroups were present in Europe far before the arrival of Roma,47 not all individuals carrying these lineages might be considered signals of gene flow between Roma and their hosts. Despite this limitation, we could identify one Roma individual with a haplotype far away from the star-like core identified as the founder J-M92 in Roma, suggesting gene flow from host to Roma (see Supplementary Figure S2D). In the case of J-M67, several Roma individuals present haplotypes distant from the founder star-like core, but only for three of them we could infer with little doubt that they show a host haplotype (Supplementary Figure S2F), suggesting again gene flow from hosts to Roma. For the other haplogroups frequent in Roma (E-V13, I-P37.2, J-M410, and R-M17), no pattern of founder lineages was found and may represent gene flow from their hosts (Supplementary Figures S2G–J). WIMP values for the founding lineages in every Roma population were variable, with very low values in Romanian and Ukrainian Roma (indicating low internal haplotype diversity) and high values in Bulgarian Balkan Roma (Figure 1a). There is a remarkable difference between Bulgarian Roma samples (Balkan and Vlax groups) that may be related to the different demographic history of Bulgarian Romani groups.14, 17
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