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  • Neutral variant and disease causing mutations

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  • 1. Genetic studies of Gypsies
  • 2. Who are they??  The Gypsies (a misnomer, derived from an early legendabout Egyptian origins) defy the conventional definition of a population.  Referred to as ‘‘the invisible minority’’.  Founder populations derived from a small number of ancestors with subsequent isolation(geographic,cultural etc.) leading to limited immigration and demographic growth mainly from with in.
  • 3.  Reduced genetic diversity and founder effect gave rise to more homogeneous basis of inherited disorders make it possible for genetic studies to treat the whole population as one large family since more likely to share same ancestral disease causing DNA variants.  Private disease causing mutations and evidence of founder effect where published in 2 independent studies in 1996 1. novel heridatory motor and sensory neuropathy type lom (HMSNL). 2 . Limb-girdle muscular dystrophy 2C.
  • 4.  Further studies in private mutations and molecular epidemiology has revealed peculiar combination of genetic homogeneity and mutation sharing by affected subjects across the Europe.
  • 5. GYPSIES through the eye of social scientists  Potential of founder populaitons to contribute to understanding gentic basis of human biengs is determined by historial demography.  Current gypsy population in Europe is 10 million under different names like ROMA,SINTI ,ROMANICHALS,KALO etc..  200 year old linguistic theory of indian origins of gypsies is widely accepted which states : 1 . Arrival in byzantine emperor to the 9-11th century AD. 2 . Settling in Balkans has taken place in13 -14th century AD, early diaspora into rest of Europe.
  • 6. Romani population size in different European countries The collection of this type of data depends on declared ethnic identity which, in the case of the Roma, can be affected by a number of political and social circumstances. The estimates in the figure are the average of the numbers provided by different sources, such as census data, ministries of internal affairs and human rights organizations
  • 7.  Balkans have trditonally hosted large prortion of European gypsies referred to as Balkan and Vlax Roma  They are classified on the basis of history of migration  Slavery not only played an important role in biological history of Vlax roma,but lead to mass migrations at the time of Austrian-Turkish war in early 18th century, social and economic changes in eastern Europe in 1990’s
  • 8. Did they come from central asia?  The primary unit of social organization of gypsy group resemble the professional JATIS in india.  Identity is defined by group ethonym (usally reflecting a traditional trade.  Hypothesis on origins of proto range from lowest strata of indian caste system,to mixed society of warriors fitting of the early Islamic incursions.
  • 9. Figure 2 Multilocus comparison between Romani populations from different European countries, autochthonous Euro- pean populations and populations from north India The polymorphic systems included in the analysis comprised A1A2BO, MN, haptoglobin and Rh (CDE), with a total of 11 independent alleles. Information on these markers was available for the Roma in Slovakia (n = 350) [26], Hungary (n = 507) [11], England (n = 109) [23], Slovenia (n = 350) [27], Sweden (n = 115) [24] and Wales (n = 84) [22], for non-Roma Europeans (n = 5169) and for two north Indian populations, Rajput (n = 175) [34,35] and Punjabi (n = 140) [35,36]. Genetic distances between pairs of populations were computed by means of Reynold's coancenstry coefficient [84] and displayed as a neighbour-joining tree [85]. The robustness of the branches in the tree was assessed with a bootstrap approach [86]. The analysis was conducted using the PHYLIP 3.57c package [87].
  • 10. Picture emerging from recent genetic studies  Genetic variation of gypsy has been studied in divergent gypsy groups.  The analysis include polymorphisms on parentally inherited 1) Y CHROMOSOME 2)MITOCHONDRIAL (mt) DNA (haplogroup H-M82) (haplogroup M) 3)BIPARENTALLY INHERITED AUTOSOMAL MARKERS (pathogenic 1267deIG mutation in CHRNE)
  • 11.  Y chromosome and mt DNA haplogroups reflect the ancient human history which is used to compare global diversity data to trace continental origins of gypsy lineages.  Y chromosomal minisatellite mm (MSY1) and sequence variation in mitochondrial control region were used asses current diversity and recent population history.  ARLEQUIN is a population genetics analysis tool used to examine genetic diversity using (parameters like observed no. of haplotypes,polymorphic sites)test demographic models based on mt DNA sequence variation and assess genetic distances between populations using no. of pairwise differences as molecular distance  The dating of historical events are based upon coalescene time analysis of Ychromosome and autosomal haplotypes
  • 12.  The above method gives us a strong evidence that 47.3% of men carry H- M82 Y-chromosomes,mt DNA haplogroup M accounts almost 30% of gypsy subjects and the mutation of1267deIG has 4% of average carrier rates .  Analysis of highly mutatable MSY1 minisatellite in Y chromosome provide further evidence of limited variatins with diversity values lower in finns, basques.  The most recent common ancestor of gypsy men lived around 39 generations ago.  The process of gradual separation carried till 6 to 8 generations ago.
  • 13. Figure 2. The origins of Gypsy Y chromosome and mtDNA haplogroups. Linguistic analysis has charted the Gypsy migration from India to Europe through the Hindu Kush, along Persia and the southern shoreline of the Caspian Sea, through the southern Caucasus (Armenia) and westwards to Anatolia and Byzantium. Genetic evidence of the geographical origins of paternal and maternal lineages in the Gypsies is based on thestudy of unique event polymorphisms of the Y chromosome (left panel) and mtDNA (right panel), compared to published data on other populations.(51 – 62) Y chromosome haplogroup H-M82 and mtDNA haplogroup M can be unambiguously assigned to Asia and the Indian subcontinent. The wide geographical distribution of the remaining lineages precludes the tracing of their origins in the Gypsy population. The internal diversity of the latter lineages points to multiple admixture events during the journey or after the arrival of the Gypsies in Europe.
  • 14. Evolution of gypsy groups into genetic subisolates  The blood purity laws are applied more rigorously between roma groups than surrounding population.  Mixed marriages can result in formation of new gypsy group EX. Jewish roma was born in the common deportation camps during WW II.  Strongest genetic indication of severly lmited inherited migration is provided by the study of chromosomal haplotypes surrounding R148X founder mutation in Vlax roma groups,carrier rates ranging from 10-16%.  The lack of strict sharing of haplotypes is evidence for inter-group endogamy.  Harsh conditions of nomadic life affected the life expectancy,population growth and genetic diversity.
  • 15. Figure 3. Paternal and maternal lineages in Roma groups from Bulgaria. Proportions of Indian Y chromosome H-M82, mtDNA haplogroup M5 and of other, admixed lineages in the Vlax Roma with a recent history of nomadism (left panel) and in the sedentary Balkan groups from Bulgaria. Ethnonym abbreviations are as shown in Figure 1. Preservation of the ancestral Y chromosome lineage is particularly strong in the Vlax compared to the Balkan Roma (two-tailed permutation test P ¼ 0.017). mtDNA lineages show greater overall diversity in not reaching statistical significance (P ¼ 0.071). A rank-test comparison of the mean growth rate values, estimated using Batwing, shows a
  • 16. impact of genetic diseases  To date 9 mendelian disorders caused by primate mutations have been discovered. 
  • 17.  The above list is not exhaustive and existence of no,of additional rare single gene disorders whose molecular bases yet to be studied.  Currently available frequency data shows that 1 in 8 subjects in gypsy population is carrier of 1 of 5 mutations tested.  These carrier rates can range from 5-16%,  These mendelian disorders are considerd to be health burden,making community –based carrier testing programs highly beneficial to public health initiative.  Reported gene frequency are high for private mutations and often exeed by an order of magnitude those for global population. Ex: galactokinase deficiency frequencies in global population is 1:150000- 1:1000000 where as in romani children it is 1:5000.
  • 18.  Incorporating population history in gene cloning stratergies has prompt the novel “Not-quite identical by descent(NQIBD) approach.  In this approach identification of mutated gene is greatly facilitated by tracing origin of mutation to recent occurring haplotype background which allowed the detection of mutation by comparing sequence of small part of critical gene region between two chromosomes of single carrier parent.
  • 19. conclusions  Medical genetics has a role to play in improving health of underprivileged and forgotten people of Europe.  Future studies of epidemiology of single gene disorder should take social organization and cultural anthropology into consideration thus targeting public health programs and contributing to understandingdemographic history of roma.
  • 20.  thank you