Bioinformatic Analysis of Evolutional Conservatism and Functional Significance of Microsatellite Alleles of Human 14Q13.2 Region Associated with Type 2 Diabetes Mellitus

Abstract

Bioinformatic Analysis of Evolutional Conservatism and Functional Significance of Microsatellite Alleles of Human 14Q13.2 Region Associated with Type 2 Diabetes Mellitus The paper deals with bioinformatic and statistical analysis of the possible functional significance of the previously shown association of several microsatellite alleles in intron 6 of the human proteasome core particle PSMA6 gene (HSMS006) and four other microsatellites localised upstream in human chromosome 14q13.2 (HSMS801, HSMS702, HSMS701, HSMS602) with type 2 diabetes mellitus in Latvia and Botnia, Finland. Genotype analysis revealed that (CAA)8/(CAA)8 homozygotes of the HSMS602 marker were never found in Type 2 diabetes patients, although 6.56% of the individuals from the control groups were the (CAA)8/(CAA)8 homozygotes. For the HSMS801 marker the (AC)21/(AC)23 genotype was never found in the case group and in the control group it was detected with a frequency 4.40%; these differences were statistically significant (P < 0.05). In contrast to the Latvian population, the distribution of genotype frequencies in cases and controls taken from the Botnian dataset was almost similar. Haplotype analysis showed that in the Latvian population besides haplotypes including alleles differently represented in case and control groups, a combination of some alleles almost equally represented in both groups formed combinations that were more characteristic of either the case group or the control group. This indicates probable independent functional significance of these haplotypes that warrants further investigation. In the Botnian population, more allele combinations were observed, and the distribution of haplotypes in case and control groups differed from that observed in Latvia. The observed haplotype distributions might reflect differences between the studied populations: a homogenous and isolated Botnian vis-à-vis a mixed Latvian population. Linkage disequilibrium (LD) analysis of data on the Latvian population revealed nine of ten two-allele combinations manifesting a high LD. HSMS006 and HSMS602 combination had a low LD; among the analysed markers these were situated at the largest distance from one another. Data on the Botnian population showed that haplotypes in eight of ten combinations had a high LD, including the HSMS006 and HSMS602 combinations. It appears that the two populations differ also in linkage disequilibrium of two-loci haplotypes. Theoretical analysis of a potential functional role of the polymorphisms indicated the significance of the microsatellite length of HSMS602 and HSMS006 for the formation of DNA hairpins. The whole genomic region appears to be conservative in mammals.

Identification of a Novel Candidate Locus for Juvenile Idiopathic Arthritis at 14q13.2 in the Latvian Population by Association Analysis with Microsatellite Markers

“…(2) A false-positive result could arise from the population stratification. However, the 14q13.2 region analyzed is a highly evolutionary conserved locus with a high level of the synteny in mammals in the structure of the genes analyzed (including intronic MS) (Sjakste et al, 2008). Significant geographic variation in the locus was not observed when we previously compared the distribution of the same markers in the Latvian and Finnish populations (Sjakste et al, 2007).…”

“…MS are considered to be important functional elements of the genome as participants of the nuclear matrix anchorage sites (Boulikas, 1993), tissue-specific matrix attachment sites (Lenartowski and Goc, 2002), and binding sites with vimentin and glial fibrillary acidic protein (Tolstonog et al, 2000). Simple MS repeats can give rise to complex DNA spatial structures of functional significance (Rothenburg et al, 2001a(Rothenburg et al, , 2001bLi et al, 2003;Tolstonog et al, 2005;Sjakste et al, 2008). MS appear to be important components of insulators (Filippova et al, 2001), silencers (Rothenburg et al, 2001a(Rothenburg et al, , 2001b, and enhancers (Bassuny et al, 2003).…”

Structural and functional significance of microsatellites

“…In the HSMS602 marker, a increase in the CAA repeat number up to 10 triggers the changes in DNA secondary structure different from that of (CAA)7 and (CAA)8 alleles. In the HSMS006 microsatellite an increase in the TG repeat number from 17 to 18 is followed by a change in the hairpin structure [20]. Microsatellites identified in the vimentinbinding DNA also are capable to form hairpins [21].…”