Ancient Recombination Events Research Articles

DQA1 and DQB1 promoter diversity and linkage disequilibrium with class II haplotypes in Mexican Mestizo population.

The upstream sequences in the 5' flanking region of HLA class II genes, regulate their expression and contribute to the development of immunological diseases. We analyzed 105 healthy unrelated Mexican Mestizos for QAP and QBP polymorphism. DNA typing for DRB1, DQA1, DQB1, QAP1 and QBP1 was done using a standardized PCR-SSOP. Although all QAP alleles previously described were found in Mexicans, the distribution differed as compared to other populations. QAP-3.1, 4.1 and 4.2 were the most frequent alleles and were associated with DQA1*03, *0501 and *0402 respectively. The prevalent QBP alleles were 3.21, 3.1 and 4.1 found mainly associated with DQB1*0302, *0301 and *0501. Linkage disequilibria between the promoter and the corresponding DQA1 and DQB1 allele, are in general the same as described by others. A total of 61 different haplotypes were defined, only six of them with a frequency above 4%. The haplotypes DRB1*0407-QAP-3.1-DQA1*03-QBP-3.21-DQB1*0302 (HF = 14.37%) and DRB1*0802-QAP-4.2-DQA1*0401-QBP-4.1-DQB1*0402 (HF = 14.22%), which have an Amerindian ancestry, are the most frequent in Mexicans. Some rare combinations were detected such as DRB1*0405-QAP-1.3-DQA1*0101/4-QBP-5.11/5.12-DQB1*0501 and DRB1*0403-QAP-3.2-DQA1*03-QBP-3.21-DQB1*0302, probably due to ancient recombination events. This knowledge is relevant as a basis to evaluate functional implications and to explore the role of promoter diversity in disease expression.

Positional Cloning of the CLN5 Gene Defective in the Finnish Variant of the LINCL

Neuronal ceroid lipofuscinoses (NCLs) in children are progressive encephalopathies inherited as autosomal recessive traits. Progressive neuronal damage leads to psychomotor deterioration, visual failure, seizures, and finally to premature death. Based on the clinical course of the disease, the childhood forms can be divided into several subtypes. A variant form of the late infantile NCL (vLINCL), characterized by mental retardation, visual failure, ataxia, myoclonia, and death between the ages of 13 and 30 years, is prevalent in Finland. Information on ancient recombination events in disease alleles rising from this isolated population provided an efficient tool for refining the initial assignment of the CLN5 locus. Here we describe the steps resulting in the identification of the novel gene, defective in vLINCL.

RNAs from genetically distinct retroviruses can copackage and exchange genetic information in vivo.

Sequence analysis suggests that ancient recombination events may have occurred between genetically distinct retroviruses. An experimental system was utilized to explore the genetic interaction between different viruses. Moloney murine sarcoma virus and spleen necrosis virus are type C retroviruses that belong to different subgenera. With vectors containing packaging signals from these two viruses, DNA proviruses containing genetic information from both RNAs can be generated. This is the first experimental evidence to indicate that RNA from different retroviruses can copackage and exchange genetic information.

Tracing an ancestral mutation: genealogical and haplotype analysis of the infantile onset spinocerebellar ataxia locus.

Infantile onset spinocerebellar ataxia (IOSCA) is a progressive neurological syndrome exhibiting an autosomal recessive pattern of inheritance. The characteristic features were described in Finland in the beginning of 1990s. Having shown that IOSCA does not segregate with any of the markers linked to other hereditary ataxias and thus represents a genetically distinct disease, we assigned the locus of this new hereditary ataxia to 10q23.3-q24.1. To approximate the age of the Finnish IOSCA mutation and to investigate the possible existence of more than one mutation underlying the disease, the ancestors of 13 IOSCA families were identified by use of church records dating back to the 1500s. The IOSCA pedigrees were frequently merged, providing support for these having one common ancestor. Analysis of the extended IOSCA haplotypes exposed ancient recombination events and revealed one core haplotype of four markers on a region of approximately 2 cM, which was unequivocally present in 92% of disease chromosomes. Both genealogical and haplotype data thus suggest that a single IOSCA ancestral mutation was introduced into the Finnish population most probably approximately 30-40 generations ago before the time when the general east-west migration took place within Finland.

Efficient Construction of a Physical Map by Fiber-Fish of the CLN5 Region: Refined Assignment and Long-Range Contig Covering the Critical Region on 13q22

The variant form of late infantile neuronal ceroid lipofuscinosis (vLINCL, locus definition CLN5) represents a progressive brain disease with autosomal recessive inheritance. We have previously assigned the CLN5 locus to chromosome 13q21.1–q32 between markers D13S160 and D13S162 by linkage analysis in Finnish families. The information on ancient recombination events obtained from linkage disequilibrium provided an efficient tool for further refining the assignment of the CLN5 locus. Isolation of two novel (CA)nmarkers, COLAC1 and AC224, resulted in a dramatic restriction of the critical DNA region. We utilized the Fiber-FISH technique to orient and order the large DNA clones isolated by STSs and were able to eliminate almost totally the restriction digestion and PFGE step in the construction of the long-range DNA contig. Both linkage disequilibrium data and Fiber-FISH analyses assigned the CLN5 locus to a well-defined 200-kb region. Here we report a complete physical map of about 350 kb covering the critical chromosomal region of CLN5, which will facilitate the final isolation of the CLN5 gene.

Mapping the Friedreich ataxia locus (FRDA) by linkage disequilibrium analysis with highly polymorphic microsatellites

The Friedreich's ataxia locus (FRDA) is tightly linked to markers D9S5 and D9S15 located in 9g13-q21. Cumulated maximum lod scores between FRDA and D9S5 and between FRDA and D9S 15 are above 36 and 61, respectively, at a recombination fraction of 0, indicating that recombination events needed to orient the search of the gene are very difficult to identify and ascertain. We have established a I Megabase PFGE map around D9S5 and D9S15 and isolated a corresponding 530 kb YAC contig. We found that the two markers are 260 kb apart. This result was surprising, since D9S5 and D9S15 were independently isolated, but in agreement with the strong linkage between the two loci (lod score > 35 at a recombination fraction of 0). Seven clusters of rare cutter enzyme sites (CpG islands), which are potential indicators of genes, were identified in the 1 Megabase region by PFGE analysis and YAC mapping. The search for genes around the CpG islands is in progress. To map the Friedreich ataxia locus in the absence of clearly identified recombination events, we chose an alternative approach based on haplotype analysis of patients from small populations with precise geographic and historical origins, such as the Louisiana-Acadians, deported from Nova-Scotia about 150 years ago and who remained isolated for historical and cultural reasons. In this population, a single mutation, associated with a specific haplotype may account for the majority of Friedreich ataxia cases. Haplotypes different from the major haplotype at one or the other extremity can indicate ancient recombinations. Analysis of extended haplotypes allows therefore to scan rapidly a large number of meiosis for recombination events. We isolated, mainly from YAC clones, six multi-allelic markers (one RFLP and five CA n microsatellites) around D9S5 and D9S15. The first five polymorphisms were used to define 405 kb long haplotypes from Louisiana-Acadian patients [131. A major haplotype was found in 50% of 22 →independant affected chromosomes and this haplotype was never found on 16 normal chromosomes. Four additional “affected” haplotypes were identical to the major haplotype for alleles at FD1, 26P, GS2 and D9S15 but different for the GS4 allele. Again the four haplotypes were not found on normal chromosomes and they are very likely derived from the major haplotype by ancient recombination events. The recombinations would exclude the region beyond GS4 as a possible location for the FRDA locus. Other explanations, polymorphism instability and mutation heterogeneity, cannot be fully excluded. Another indication of an ancient recombination event between GS4 and FRDA is given by a patient from a family with known remote consanguinity, who is homozygous for a rare haplotype that shows divergence at GS4. Extension of the haplotypes with the new microsatellite markers should allow to reinforce the present conclusions, as well as identify new recombinant haplotypes in order to narrow down the localization of the Friedreich ataxia gene.