In the U.S. the frequency of ist cousin marriages is a 0.001 p(affected because of 1st cousin mating)=1/16 9 10-3=6.3 x 10-9 p(affected because of random mating)=10-8 Thus, Ml/3 of affected individuals will come from 1st cousin marriages Note that this proportion depends on allele frequency such that traits caused by very rare alleles will more often be the result of consanguinity For rare diseases, it is often quite difficult to tell whether or not they are of genetic origin. A useful method to identify disorders that are likely to be inherited is to ask whether an unusually high proportion of affected individuals have parents that are related to one another Now lets consider the problem of recessive lethal mutations in the genome We have already seen that the frequencies of recessive, loss of function alleles are usually in the range of 10-3-10-4 This may seem like a comfortably small number but given that the total number of human genes is about 2 x 104, each of us must be carrying many recessive alleles. Assuming that about 50% of genes are essential, each person should carry an average of approximately 1-10 recessive lethal mutations Genetic Load: lethal equivalents per genome Usually the genetic load is not a problem since it is very unlikely that both parents will happen to have lethal mutations in the same genes. However, that chance is considerably increased for parents that are 1st cousins As we have already calculated, the probability that a grandparental allele will become homozygous is /64 for 1st cousins Thus, each recessive lethal allele for which one of the grandparents in a carrier will contribute an increased probability of 0.016 that the grandchild will be homozygous and therefore be afflicted by a lethal inherited defect To look for this effect we will use the frequency of stillbirth or neonatal death from 1st cousin marriages. We must also be careful to subtract the background frequency of stillbirths and neonatal deaths that are not due to genetic factors. These frequencies an be obtained from the cases where parents are not relatedIn the U.S. the frequency of 1st cousin marriages is ≈ 0.001 p (affected because of 1st cousin mating) = 1/16 q 10-3 = 6. 3 x 10-9 p (affected because of random mating) = 10-8 Thus, ~1/3 of affected individuals will come from 1st cousin marriages Note that this proportion depends on allele frequency such that traits caused by very rare alleles will more often be the result of consanguinity For rare diseases, it is often quite difficult to tell whether or not they are of genetic origin. A useful method to identify disorders that are likely to be inherited is to ask whether an unusually high proportion of affected individuals have parents that are related to one another. Now let's consider the problem of recessive lethal mutations in the genome: We have already seen that the frequencies of recessive, loss of function alleles are usually in the range of 10-3 - 10-4 This may seem like a comfortably small number but given that the total number of human genes is about 2 x 104, each of us must be carrying many recessive alleles. Assuming that about 50% of genes are essential, each person should carry an average of approximately 1-10 recessive lethal mutations! Genetic Load: lethal equivalents per genome. Usually the genetic load is not a problem since it is very unlikely that both parents will happen to have lethal mutations in the same genes. However, that chance is considerably increased for parents that are 1st cousins. As we have already calculated, the probability that a grandparental allele will become homozygous is 1/64 for 1st cousins Thus, each recessive lethal allele for which one of the grandparents in a carrier will contribute an increased probability of 0.016 that the grandchild will be homozygous and therefore be afflicted by a lethal inherited defect. To look for this effect we will use the frequency of stillbirth or neonatal death from 1st cousin marriages. We must also be careful to subtract the background frequency of stillbirths and neonatal deaths that are not due to genetic factors. These frequencies can be obtained from the cases where parents are not related