Sequencing and genotypic analysis of the triosephosphate isomerase (TPI1) locus in a large sample of long-lived Germans.
BACKGROUND
Triosephosphate isomerase (TPI) is a central and conserved glycolytic enzyme. In humans, TPI is encoded by a single gene on 12p13, and associated with a rare genetic disorder, TPI deficiency. Reduced TPI activity can increase specific oxidant resistances of model organisms and TPI null-alleles have been hypothesized to promote a heterozygote advantage in man. However, comprehensive genetic information about the TPI1 locus is still lacking.


RESULTS
Here, we sequenced the TPI1 locus in a sample of 357 German long-lived individuals (LLI) aged 95 to 110 years. We identified 17 different polymorphisms, of which 15 were rare and previously unknown. The two remaining SNPs occurred at much higher frequency and were tested for association with the longevity phenotype in larger samples of LLI (n = 1422) and younger controls (n = 967). Neither of the two markers showed a statistically significant difference in allele or genotype frequency between LLI and control subjects.


CONCLUSIONS
This study marks the TPI1 locus as extraordinarily conserved, even when analyzing intronic and non-coding regions of the gene. None of the identified sequence variations affected the amino acid composition of the TPI protein and hence, are unlikely to impact the catalytic activity of the enzyme. Thus, TPI variants occur less frequent than expected and inactive alleles are not enriched in German centenarians.
Ralser
Markus
M
Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany. ralser@molgen.mpg.de
Nebel
Almut
A
Kleindorp
Rabea
R
Krobitsch
Sylvia
S
Lehrach
Hans
H
Schreiber
Stefan
S
Reinhardt
Richard
R
Timmermann
Bernd
B
D000369:Aged, 80 and over; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D005858:Germany; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D014305:Triose-Phosphate Isomerase / Q000235:genetics*
D007527:Isoenzymes; D014305:Triose-Phosphate Isomerase