In silico analysis of non-synonymous single nucleotide polymorphisms in human DAZL gene associated with male infertility

In living systems the most frequent type of genetic mutation is the single nucleotide polymorphism (SNP). Non-synonymous SNPs (nsSNPs) or missense mutations arise in coding regions of a particular gene. nsSNPs result in a single amino acid substitution which may have effects on the structure and/or function of proteins. Spermatogenesis is a complex process where haploid spermatozoa are formed. The deleted in azoospermia like (DAZL) gene has a relationship with male infertility and dysfunction of DAZL may decrease the sperm count which leads to oligozoospermia or azoospermia. Various computational methods were used to analyze the genetic variations of DAZL affecting the structure and/or function. In the present study, N109T was assigned as the most deleterious or disease related nsSNP by SIFT, MutPred, PolyPhen 2.0, I-Mutant, and MuStab tools. The ConSurf tool showed that functional amino acid residues which are conserved in Human DAZL include the N109T nsSNP. The secondary and tertiary structure was predicted using PSIPRED and MUSTER. Our study shows that the N109T variant may directly or indirectly weaken amino acid interactions and hydrogen bond networks of the DAZL protein, which we predicted may result in altered DAZL protein function. Further, computational analysis of free energy change due to this point mutation using GROMOS96 indicated decreased stability of the DAZL protein. The N109T variant in an infertile male population may provide a genetic marker for mutational analysis of DAZL.

Abbreviations: DAZL: deleted in azoospermia like; dbSNP: database of single nucleotide polymorphism; nsSNPs: non-synonymous SNPs; AA: amino acid; SIFT: sorting intolerant from tolerant; PolyPhen-2: polymorphism phenotyping v2; MUSTER: multi-sources threader; PDB: protein data bank; MuStab: predicting mutant protein stability change; PSIPRED: PSI-blast based secondary structure prediction.