Two types of amino acid substitutions in protein evolution

The nucleotide sequences of the constant portions of mouse immunoglobulin -yj and Y2b genes were compared. A remarkable homology was found in a long (about 500 nucleotides) continuous segment including the entire CHI coding region and about the first half of the first intervening sequence. Furthermore, comparison of amino acid sequences of four y-class chains revealed that the CHI domain shows limited divergence among 7Y1, f2,, and IY2b. Interestingly, the homology region extends to the CH2 domain in y2y and 72b.These findings suggest that, during their evolution, a double unequal crossing-over event has taken place at different intervening sequences, resulting in the transfer of the DNA segment coding for the CHI domain or CH1-CH2 domains. A possible evolutionary implication for such an "intervening sequencemediated domain transfer" event is discussed.Immunoglobulins are composed of the heavy and light chains, each of which contains the NH2-terminal variable region and the COOH-terminal constant region. The heavy chain proteins are classified into five classes-,u y, a, 6, and c-on the basis of their primary structures in the constant region. The class of the y chain, which contains three domains and the hinge region, is divided into several subclasses such as y1, y2a, y2b, and y3 in mouse. Recent analyses by amino acid sequence determination (1-5) and nucleic acid hybridization (6) indicate that immunoglobulin genes coding for the y subclasses share considerable homology, suggesting that these genes have evolved by gene duplication of a common ancestor.Recently, we have cloned two immunoglobulin constant region genes of the y subclasses -YI and 72b from newborn mouse DNA and determined the complete nucleotide sequences, including structural, intervening, and flanking sequences (7-9). The nucleotide sequences have demonstrated that both y, and 72b chain genes are interrupted by three intervening sequences (IVSs) at the junction of the domains and the hinge region. The results are consistent with the hypothesis that IVSs and their splicing played an important role in the evolution of the eukaryotic genes (10, 11) as discussed previously (7,8,12). Comparison of the two sequences not only provided unequivocal evidence that the two genes derived from a common ancestor but also revealed several interesting structural features that might be important for recognition of RNA splicing, poly(A) addition, or termination of transcription (8).To trace the evolutionary history of the -y chain genes in greater detail we have undertaken the comparison of the two sequences for the coding and noncoding regions. We have evaluated the sequence divergence of the coding region by measuring two distinct types of substitutions: one leading to amino acid change and the other leading to synonymous change (13). Obviously, the former is under the influence of selective constraints at both protein and RNA levels and the latter is under the influence of selective constraint at the RNA level alone. Furthermore, the extent of divergenc...

Section: Methodssupporting

confidence: 55%

mentioning

confidence: 99%

Nucleotide sequence divergence of mouse immunoglobulin gamma 1 and gamma 2b chain genes and the hypothesis of intervening sequence-mediated domain transfer.

Miyata¹,

Yasunaga²,

Yamawaki-Kataoka³

et al. 1980

“…It has been suggested that positive selection tends to operate on the more conservative changes (19), whereas others argued that it works more often on the radical ones (20,21). There are two commonly used indices for the physicochemical differences between amino acids: Grantham's distance, which takes into account the volume, polarity, and carbon composition of the side chain of each amino acid (22), and Miyata's distance, which measures volume and polarity (23). Conservative changes have smaller distances than radical ones by either measure.…”

Section: Contrasting Divergence and Polymorphism For The 75 Elementarymentioning

confidence: 99%

Adaptive evolution in humans revealed by the negative correlation between the polymorphism and fixation phases of evolution

Gojobori

Tang

Akey

et al. 2007

The selective forces acting on amino acid substitutions may be different in the two phases of molecular evolution: polymorphism and fixation. Negative selection and genetic drift may dominate the first phase, whereas positive selection may become much more significant in the second phase. However, the conventional dichotomy of synonymous vs. nonsynonymous changes does not offer the resolution needed to study the dynamics of these two phases. Following previously published methods, we separated amino acid changes into 75 elementary types (1-bp substitution between their respective codons). The likelihood of each type of amino acid change becoming polymorphic (PI, which stands for ''polymorphic index''), relative to synonymous changes, can then be calculated. Similarly, the likelihood of fixation (FI, for "fixation index"), conditional on common polymorphisms, is also calculated. Using Perlegen and HapMap data on human polymorphisms and the chimpanzee sequences as the outgroup, we compared the evolutionary dynamics of the 75 elementary changes in the two phases. We found a strong ''L-shaped'' negative correlation (P < 0.001) between FI and PI. Only those changes with low PIs show FI > 1, which is often a signature of adaptive evolution. These patterns suggest that negative and positive selection operate more effectively on the same set of amino acid changes and that Ϸ10 -13% of amino acid substitutions between humans and chimpanzee may be adaptive. 2). Many studies have attempted to address this issue by considering levels of within-species polymorphism or between-species divergence (3, 4). One may gain further resolution by dividing the process of mutation substitution into two separate phases, polymorphism and fixation. When a new mutation arises in a population, it exists as a low-frequency polymorphism. In this first phase of evolution, the dominant forces are genetic drift and negative selection. If this mutation can reach a substantial frequency (say, 20% in humans), then it is unlikely to be strongly deleterious. Hence, the second phase of evolution, the process of fixation, is governed mainly by drift and positive selection. Whether these two phases are positively or negatively correlated will inform us about how natural selection operates. In this report, we shall address these questions by using human data, but the approach should be general.To investigate the evolutionary dynamics and correlation between these two phases, we need to be able to classify mutations in coding regions into more categories than the traditional nonsynonymous and synonymous dichotomy. We follow the procedure developed by Tang et al. (refs. 5 and 6, see also ref. 7), who classified amino acid changes into 75 elementary types. An elementary amino acid change is one that can be reached by 1-bp substitution in the codons (Phe to Leu, for example). The rest of the 115 types are all composites of two or three elementary changes (Phe to Pro, for example). One can then ask how these 75 elementary changes differ in their likelihoods of ...

“…In contrast, we find that negative selection among nonsynonymous polymorphisms is widespread, and that the strength of negative selection on nonsynonymous sites is predicted by several measures of amino acid exchangeability, i.e., ''radical'' amino acid mutations tend to be more deleterious than ''conservative'' changes. Several methods have been proposed for quantifying the impact of different types of amino acid changes on protein structure and function (16)(17)(18)(19)(20)(21)(22); examples of different criteria that are used include physicochemical properties of the change, phylogenetic patterns of substitution, and experimental measures of the effect of different substitutions on protein structure and activity. However, the relationship between these measures and evolutionary fitness has not been fully explored.…”

mentioning

confidence: 99%

Simultaneous inference of selection and population growth from patterns of variation in the human genome

Williamson

Hernández

Fledel-Alon

et al. 2005

325

370

Natural selection and demographic forces can have similar effects on patterns of DNA polymorphism. Therefore, to infer selection from samples of DNA sequences, one must simultaneously account for demographic effects. Here we take a model-based approach to this problem by developing predictions for patterns of polymorphism in the presence of both population size change and natural selection. If data are available from different functional classes of variation, and a priori information suggests that mutations in one of those classes are selectively neutral, then the putatively neutral class can be used to infer demographic parameters, and inferences regarding selection on other classes can be performed given demographic parameter estimates. This procedure is more robust to assumptions regarding the true underlying demography than previous approaches to detecting and analyzing selection. We apply this method to a large polymorphism data set from 301 human genes and find (i) widespread negative selection acting on standing nonsynonymous variation, (ii) that the fitness effects of nonsynonymous mutations are well predicted by several measures of amino acid exchangeability, especially site-specific methods, and (iii) strong evidence for very recent population growth. N atural selection alters observed patterns of genetic variation within species. For instance, negative selection against slightly deleterious mutations leads to a relative excess of rare variants in a population (1), recurrent positive selection leads to a relative excess of common variants (2), and balancing selection can cause an increase of mutations at intermediate frequencies (3,4). Because different types of natural selection have different effects on observed genetic variation, it should, in principle, be possible to infer the strength and mode of natural selection from patterns of variation in samples of DNA sequences.However, a major complicating factor in the effort to infer selection from sequence data is that demographic forces, such as recent population growth, bottlenecks, and subdivision, also affect observed patterns of genetic variation in a manner that can mimic the effects of natural selection (Fig. 3, which is published as supporting information on the PNAS web site). For example, recent population growth, like weak negative selection, leads to a relative excess of rare mutations (5, 6), and certain models of population structure produce an effect identical to that of balancing selection (7). In general, one can only be confident of inferences regarding selection if the ''signature'' of selection is unique, compared with the effects of other forces. Given that most populations fluctuate in size and do not mate randomly, there is now a growing realization that one must account for demography while inferring selection (8).Because demographic forces have similar effects over the whole genome, one useful way to account for demography while inferring selection is to compare patterns of variation among different functional classes of mutati...