Probability of detection of genotyping errors and mutations as inheritance inconsistencies in nuclear-family data
Douglas, J.A.; Skol, A.D.; Boehnke, M.
American Journal of Human Genetics 70(2): 487-495
Gene-mapping studies routinely rely on checking for Mendelian transmission of marker alleles in a pedigree, as a means of screening for genotyping errors and mutations, with the implicit assumption that, if a pedigree is consistent with Mendel's laws of inheritance, then there are no genotyping errors. However, the occurrence of inheritance inconsistencies alone is an inadequate measure of the number of genotyping errors, since the rate of occurrence depends on the number and relationships of genotyped pedigree members, the type of errors, and the distribution of marker-allele frequencies. In this article, we calculate the expected probability of detection of a genotyping error or mutation as an inheritance inconsistency in nuclear-family data, as a function of both the number of genotyped parents and offspring and the marker-allele frequency distribution. Through computer simulation, we explore the sensitivity of our analytic calculations to the underlying error model. Under a random-allele-error model, we find that detection rates are 51%-77% for multiallelic markers and 13%-75% for biallelic markers; detection rates are generally lower when the error occurs in a parent than in an offspring, unless a large number of offspring are genotyped. Errors are especially difficult to detect for biallelic markers with equally frequent alleles, even when both parents are genotyped; in this case, the maximum detection rate is 34% for four-person nuclear families. Error detection in families in which parents are not genotyped is limited, even with multiallelic markers. Given these results, we recommend that additional error checking (e.g., on the basis of multipoint analysis) be performed, beyond routine checking for Mendelian consistency. Furthermore, our results permit assessment of the plausibility of an observed number of inheritance inconsistencies for a family, allowing the detection of likely pedigree-rather than genotyping-errors in the early stages of a genome scan. Such early assessments are valuable in either the targeting of families for resampling or discontinued genotyping.