Human F7 sequence is split into three deep clades that are related to FVII plasma levels

Hum Genet. 2006 Feb;118(6):741-51. doi: 10.1007/s00439-005-0045-5. Epub 2005 Nov 16.

Abstract

It is widely accepted that FVII levels are strongly, consistently, and independently related to cardiovascular risk. These levels are influenced by genetic and environmental factors. Among the genetic factors, only a limited number of polymorphisms in the F7 gene have been reported, and they explain only a small proportion of the genetic variability. Recently, we have accomplished the complete dissection of the F7 quantitative trait locus responsible for all of the genetic variability observed in FVII levels. Now, we present the thorough study of the haplotype organization of F7 DNA sequence variation among individuals and the evolutionary processes that produced this variation, by sequencing 15 kb of genomic DNA sequence from the F7 locus in 40 unrelated individual (80 chromosomes) from the genetic analysis of idiopathic thrombophilia (GAIT) project as well as four non-human primate species. Our study revealed 49 polymorphisms, of which 39 SNPs were further considered. Genotyping of these DNA variations in the whole family-based GAIT sample helped resolve linkage phases, and a total of 37 distinct haplotypes were identified.Tajima's D was significantly positive in this sample, suggesting balancing selection. This parameter was a reflection of the phylogenetic structure of F7 haplotype, which was deeply split into three well-supported clades or haplogroups, suggesting that functional differences among F7 variants do not depend on a few single-site variations. Moreover, haplogroup 2 was associated with high FVII levels and haplogroup 3 with low levels. In this study, we have for the first time established a clear relation between genotypic variability structure and phenotypic variability of a particular quantitative trait involved in a complex disease.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Evolution, Molecular*
  • Factor VII / analysis*
  • Factor VII / genetics*
  • Gorilla gorilla
  • Haplotypes
  • Humans
  • Molecular Sequence Data
  • Pan paniscus
  • Pan troglodytes
  • Phenotype
  • Phylogeny
  • Polymorphism, Single Nucleotide*
  • Pongo pygmaeus
  • Sequence Homology, Nucleic Acid

Substances

  • Factor VII