Screening for deletions in the KLK gene family using small pedigrees
Null alleles for PCR-based genetic markers can either be due to polymorphisms in the primer annealing sites or to deletions. When analysing diseases with a complex inheritance, the detection of deletions is very important, since deletions may in many cases directly contribute in the causation of disease. Deletions outside coding regions and other null alleles are also of interest, since undetected they may cause errors in haplotype inference and population genetic analyses. Null alleles can be detected as a special case of non-Mendelian inheritance, i.e. when a parent and child appear to be homozygous for different alleles. The probability for this event was derived for: one parent and one child, a trio, a trio with one grandparent and a trio with two grandparents. The power to detect a deletion for a fixed overall number of investigated individuals was calculated for SNPs and multiallelic markers with varying allele frequencies. The results show that for SNPs, a trio with two grandparents are always more efficient than the other family types despite a lower total number of founder chromosomes. We screened for deletions in the Kallikrein (KLK) gene family using 41 three-generation pedigrees containing 4-5 individuals. We genotyped 97 SNPs covering all 15 KLK genes encompassing a region of 263 kb, i.e. the average intermarker distance was 2.7 kb. Several cases of segregating null alleles were detected. At least one of them is a deletion and further investigations are underway to determine the nature of the other null alleles. A maximum likelihood estimate of the allele frequencies indicate a population frequency of approximately 6% for the confirmed deletion.