Until around 1990, most multigene families were thought to be subject to concerted evolution, in which all member genes of a family evolve as a unit in concert. However, phylogenetic analysis of MHC and other immune system genes showed a quite different evolutionary pattern, and a new model called birth-and-death evolution was proposed. In this model, new genes are created by gene duplication and some duplicate genes stay in the genome for a long time, whereas others are inactivated or deleted from the genome. Later investigations have shown that most non-rRNA genes including highly conserved histone or ubiquitin genes are subject to this type of evolution. However, the controversy over the two models is still continuing because the distinction between the two models becomes difficult when sequence differences are small. Unlike concerted evolution, the model of birth-and-death evolution can give some insights into the origins of new genetic systems or new phenotypic characters.

/pdf/concerted-and-birth-and-death-evolution-of-multigene-59ik8yal3k.pdf

Concerted and birth-and-death evolution of multigene families.

BASE composition is spatially structured in mammalian genomes. From sodium chloride centrifugation experiments, Bernardi et al . ([1985][1]) defined three major classes of genomic fragments with low, median, and high GC content, respectively, and called them isochores. This discrete description now

https://www.genetics.org/content/genetics/159/2/907.full.pdf

GC-Content Evolution in Mammalian Genomes: The Biased Gene Conversion Hypothesis

Gene conversion is often invoked to explain the evolution of sequence patterns observed in major histocompatibility complex (MHC) genes and their alleles. This is the gene conversion hypothesis of MHC sequence evolution. These observations and their interpretation probably belong in a larger theoretical framework, namely the evolution of systems of resistance to rapidly evolving pathogens. This review looks critically at the evidence in favor of the gene conversion hypothesis in this context. We conclude that the case for the existence of an adaptive mechanism in the MHC favoring gene conversion mutations is not proven.

The gene conversion hypothesis of MHC evolution: a review

Evidence for the adaptive evolution of mutation rates.

Copy number variable regions (CNVRs) can result in drastic phenotypic differences and may therefore be subject to selection during domestication. Studying copy number variation in relation to domestication is highly relevant in pigs because of their very rich natural and domestication history that resulted in many different phenotypes. To investigate the evolutionary dynamic of CNVRs, we applied read depth method on next generation sequence data from 16 individuals, comprising wild boars and domestic pigs from Europe and Asia. We identified 3,118 CNVRs with an average size of 13 kilobases comprising a total of 39.2 megabases of the pig genome and 545 overlapping genes. Functional analyses revealed that CNVRs are enriched with genes related to sensory perception, neurological process and response to stimulus, suggesting their contribution to adaptation in the wild and behavioral changes during domestication. Variations of copy number (CN) of antimicrobial related genes suggest an ongoing process of evolution of these genes to combat food-borne pathogens. Likewise, some genes related to the omnivorous lifestyle of pigs, like genes involved in detoxification, were observed to be CN variable. A small portion of CNVRs was unique to domestic pigs and may have been selected during domestication. The majority of CNVRs, however, is shared between wild and domesticated individuals, indicating that domestication had minor effect on the overall diversity of CNVRs. Also, the excess of CNVRs in non-genic regions implies that a major part of these variations is likely to be (nearly) neutral. Comparison between different populations showed that larger populations have more CNVRs, highlighting that CNVRs are, like other genetic variation such as SNPs and microsatellites, reflecting demographic history rather than phenotypic diversity. CNVRs in pigs are enriched for genes related to sensory perception, neurological process, and response to stimulus. The majority of CNVRs ascertained in domestic pigs are also variable in wild boars, suggesting that the domestication of the pig did not result in a change in CNVRs in domesticated pigs. The majority of variable regions were found to reflect demographic patterns rather than phenotypic.

/pdf/evolutionary-dynamics-of-copy-number-variation-in-pig-4lxsakyart.pdf

Evolutionary dynamics of copy number variation in pig genomes in the context of adaptation and domestication

We examined 32 DNA sequences of mouse and human major histocompatibility complex (MHC) genes believed to have been subjected to gene conversion events. All regions of the mouse H2 genes as well as the human HLA genes which have been implied to be involved in gene conversion events had elevated levels of CpG dinucleotides, whereas the rest of the genes showed extensive CpG suppression. Mouse MHC genes which have been suspected but not directly implied to be involved in gene conversion events also showed elevated levels of CpG dinucleotides. Moreover, both mouse and human MHC genes which have never been suspected of undergoing gene conversion had low levels of CpG throughout the genes. These results indicate that high CpG levels are correlated with gene conversion rather than with polymorphism, as non-polymorphic genes that have been implicated as gene conversion donors also have elevated levels of CpG dimers in the involved regions, whereas polymorphic genes which have never been considered to undergo gene conversion events have a low level of CpG dinucleotides. We also studied the methylation pattern of CpG dimers in the Abk gene by restriction enzyme digestion of mouse testis DNA followed by Southern blot and hybridization to an Abk-specific probe. The examined CpG dimers in prepubescent mice, where the latest germline stages are spermatogonia, leptene, or pachytene, are respectively non-methylated. Accordingly, the CpG dimers appear to be non-methylated in germline DNA from the testis of prepubescent mice, where gene conversions have been reported to occur.

Gene conversion of major histocompatibility complex genes is associated with CpG-rich regions

We have explored the effects of γ-irradiation and etoposide on the gene conversion frequency between the endogenous major histocompatibility complex class II genes Abk and Ebd in a mouse testis cell line of non-germline origin with a polymerase chain reaction assay. Both γ-rays and etoposide were shown to increase the gene conversion frequency with up to 15-fold compared to untreated cells. Etoposide, which is an agent that stabilise a cleavable complex between DNA and DNA topoisomerase II, shows an increased induction of gene conversion events with increased dose of etoposide. Cells treated with γ-rays, which induce strand breaks, had an increased gene conversion frequency when they were subjected to low doses of irradiation, but increasing doses of irradiation did not lead to an increase of gene conversion events, which might reflect differences in the repair process depending on the extent and nature of the DNA damage. These results where DNA damage was shown to be able to induce gene conversion of endogenous genes in mouse testis cells suggests that the DNA repair system could be involved in the molecular genetic mechanism that results in gene conversion in higher eukaryotes like mammals.

DNA damage caused by etoposide and γ-irradiation induces gene conversion of the MHC in a mouse non-germline testis cell line

The non-obese diabetic (NOD) mouse is an animal model for insulin- dependent diabetes that has many similarities to the human disease. NOD mice transgenic for the Ea gene, allowing expression of th ...

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2567.1998.00580.x

Disease-protected major histocompatibility complex Ea-transgenic non-obese diabetic (NOD) mice show interleukin-4 production not seen in susceptible Ea-transgenic and non-transgenic NOD mice.

The E complex of the major histocompatibility complex (MHC) can prevent the spontaneous development of diabetes in nonobese diabetic (NOD) mice transgenic for the Ea gene. None of three promoter-mutated Ea constructs with Ea expression directed to different subsets of immunocompetent cells exerts full protection in NOD mice. The promoter-mutated constructs are all capable of mediating intrathymic elimination of I-E-restricted T cells. Thus, thymic negative selection is not responsible for the protective effect but a more complex effect is likely. Here we show that combinations of two or three different mutated Ea constructs do not protect against intra-islet insulitis either. We also show that spleen cells from protected animals are sufficient to protect NOD mice in adoptive transfer experiments. The only detectable expression defects in splenic cells or cells influencing the repertoire of splenic cells are in the B-cell compartment. Furthermore, in three construct combinations, the differences to wild-type expression are extremely small. Thus, we conclude that even minute disturbances of the E expression pattern might reduce the protection of NOD mice from insulitis.

Minute defects in the expression of MHC E molecules lead to impaired protection from autoimmunity in NOD mice.

E expression is needed on both bone marrow derived cells and thymic epithelium to increase IL-4 production and achieve protection in NOD bone marrow chimeras.

Jan Böhme

Papers

Gene conversion of major histocompatibility complex genes is associated with CpG-rich regions

DNA damage caused by etoposide and γ-irradiation induces gene conversion of the MHC in a mouse non-germline testis cell line

Disease-protected major histocompatibility complex Ea-transgenic non-obese diabetic (NOD) mice show interleukin-4 production not seen in susceptible Ea-transgenic and non-transgenic NOD mice.

Minute defects in the expression of MHC E molecules lead to impaired protection from autoimmunity in NOD mice.

E expression is needed on both bone marrow derived cells and thymic epithelium to increase IL-4 production and achieve protection in NOD bone marrow chimeras.