THE RELATION OF RECOMBINATION TO MUTATIONAL ADVANCE
The method of calculation is shown whereby a formula has been derived that states approximately the ratio of the rate of accumulation of advantageous mutant genes in a population that undergoes recombination to the rate in an otherwise nonrecombining one. A table is given showing the ratios thus found for different frequencies of advantageous mutations and different degrees of their advantage. I t is shown that this calculation does not apply for mutant genes that act advantageously only when in some special combinations with one or more other mutant ,genes, and that as far as these cases of special synergism are concerned recombining lines have no evolutionary advantage over non-recombining ones. Other limitations of the formula are pointed out and assessed. I t is explained that most factors that retard the rate of recombination--for example, linkage, rari ty of outbreeding, intercalation of sexual reproduction between more frequent cycles of asexual propagation, and partial isolation between subpopulat ions--must usually cause little long-term retardation of the speed of advance that is fostered by recombination. Moreover, even where long-term evolution has virtually ceased, recombination of mutant genes still confers upon a population the means of adopting short-term genetic "dodges", that adjust it to ecological and "physical" changes in its circumstances, much more rapidly than would be possible for a comparable asexual population. Under conditions where only stability of type is needed, a non-recombining population does not actually degenerate as a result of an excess of mutation over selection, after the usual equilibrium between these pressures is reached. However, a kind of irreversible ratchet mechanism exists in the non-recombining species (unlike the recombining ones) that prevents selection, even if intensified, from reducing the mutational loads below the lightest that were in existence when the intensified selection started, whereas, contrariwise, "drif t" and what might be called "selective noise" must allow occasional slips of the lightest loads in the direction of increased weight.
Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies.
The basic steps as well as the merits of linkage investigations have recently been summarized [1]. A very simple method to test for genetic linkage is the sib-pair method of Penrose [2] which tests for independence of the phenotypes at two loci. Linkage between these two loci leads to a small deviation from independence of the phenotypes in each sibship. However, this method is rather inefficient and does not estimate the recombination fraction. Furthermore, there may be causes other than linkage leading to a deviation from independence and thus simulating the effects of linkage. Maximum-likelihood estimation of the recombination fraction in man was introduced in two basic papers by Haldane and Smith [3] and Smith [4]. Likelihood methods can be shown to extract all possible information from the phenotypes in pedigrees. These methods require the computation of the probability that, considering all possible outcomes in a certain pedigree, phenotypes turn out to be as actually observed. This probability is called the likelihood of the pedigree, and its value largely depends on the recombination fraction. The essential difficulty in computing this likelihood is that the recombination fraction specifies the probabilities of genotypes, not phenotypes. Since phenotypes are functions of the genotypes, the likelihood can be expressed as a weighted sum over all genotypes compatible with the observed phenotypes, each summand being the probability of the given configuration of genotypes in the pedigree multiplied by the probability of the phenotypes given the genotypes [3]. Even for pedigrees of moderate size, this summation can involve a large number of terms. For certain types of 2-generation families, Morton [5] has computed and tabulated the likelihoods in the form of so-called lod scores. These lods can be easily used if a pedigree is of suitable type. However, in a pedigree with several generations, extraction of all information requires computation of the full likelihood. These laborious calculations have been undertaken by Morton in his investigation on the linkage between elliptocytosis and Rh [6]. Several attempts have been made to have computers do this work [7-10].
Molecular mechanism of class switch recombination: linkage with somatic hypermutation.
Class switch recombination (CSR) and somatic hypermutation (SHM) have been considered to be mediated by different molecular mechanisms because both target DNAs and DNA modification products are quite distinct. However, involvement of activation-induced cytidine deaminase (AID) in both CSR and SHM has revealed that the two genetic alteration mechanisms are surprisingly similar. Accumulating data led us to propose the following scenario: AID is likely to be an RNA editing enzyme that modifies an unknown pre-mRNA to generate mRNA encoding a nicking endonuclease specific to the stem-loop structure. Transcription of the S and V regions, which contain palindromic sequences, leads to transient denaturation, forming the stem-loop structure that is cleaved by the AID-regulated endonuclease. Cleaved single-strand tails will be processed by error-prone DNA polymerase-mediated gap-filling or exonuclease-mediated resection. Mismatched bases will be corrected or fixed by mismatch repair enzymes. CSR ends are then ligated by the NHEJ system while SHM nicks are repaired by another ligation system.
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