Question

The germline mutation rates tend to increase along with a later replication time. Please support this with specific examples (ie genes that have high germline mutation rates and have a late replication time)

Answer 1

Human genome undergoes greater than 20 mitotic replications and 1 meiotic replication when it is passed on from one generation to the next generation. A number of mitotic replications further give rise to somatic cells. Errors can occur in each of these steps. The rate at which errors in transmission of genetic information from one generation to another occurs is known as germline mutation rate. Germline mutation rate in humans is nearly 0.5×10^?9 per basepair per year. Euchromatin replicates faster than heterochromatin.

Human DNA replication has multiple origins of replication. Hence, different regions of the genome replicate at different timings. Factors affecting mutation rate are replication timing (rt), meiotic recombination rate, GC content, DNA accessibility, and distance from the telomeres.

A large amount of heterochromatin has repetitive DNA sequences and transposable elements (TE). These sequences vary in a lineage-specific manner with a high mutation rates. Human FRA3B locus lacks replication origin and is replicated later is S phase. If replication origins are in flanking regions of a late replicating region, the replication may remain incomplete at end of S phase. Such incomplete replication may lead to deletions of genes in daughter cells. For example, deletions occur at FRA3B and FRA16D locus. Two genes FHIT and WWOX may be inactivated in many human cancers. The FRA16 D fragile site exhibits high germline mutations due to translocations. The MAF proto-oncogene that is located nearly 1 Mb distal region is deregulated in many myeloma cancers.

The regions that replicate later in the genome are known to be associated with a large number of SNPs in humans. Point mutations are therefore enriched in late replicating regions. Late phases of replication are faster and less structured and hence, more prone to errors or mutations. It is associated with increased breakage of DNA at common sites. The activity of error-prone DNA polymerases in late-replicating regions may be responsible for some of the higher germline transmission rate. Polymerase zeta (pol ?), is an essential error-prone polymerase that causes transversions. It can also cause dinucleotide mutations (DNMs). The pol ? can form more GC?AA/TT DNMs.