The Genetic Background Effect on Domesticated Species: A Mouse Evolutionary Perspective

Laboratory mouse strains are known for their large phenotypic diversity and serve as a primary mammalian model in genotype-phenotype association studies. One possible attempt to understand the reason for this diversity could be addressed by careful investigation of the unique evolutionary history of their wild-derived founders and the consequence that it may have on the genetic makeup of the laboratory mouse strains during the history of human fancy breeding. This review will summarize recently published literature that endeavors to unravel the genetic background of laboratory mouse strains, as well as give new insights into novel evolutionary approaches. I will explain basic concepts of molecular evolution and the reason why it is important in order to infer function even among closely related wild and domesticated species. I will also discuss future frontiers in the field and how newly emerging sequencing technologies could help us to better understand the relationship between genotype and phenotype

The consequence of natural selection on genetic variation in the mouse

AbstractLaboratory mouse strains are known to have emerged from recent interbreeding between individuals of Mus musculus isolated populations. As a result of this breeding history, the collection of polymorphisms observed between laboratory mouse strains is likely to harbor the effects of natural selection between reproductively isolated populations. Until now no study has systematically investigated the consequences of this breeding history on gene evolution. Here we have used a novel, unbiased evolutionary approach to predict the founder origin of laboratory mouse strains and to assess the balance between ancient and newly emerged mutations in the founder subspecies. Our results confirm a contribution from at least four distinct subspecies. Additionally, our method allowed us to identify regions of relaxed selective constraint among laboratory mouse strains. This unique structure of variation is likely to have significant consequences on the use of mouse to find genes underlying phenotypic variation

Mouse SNP Miner: an annotated database of mouse functional single nucleotide polymorphisms

BACKGROUND: The mapping of quantitative trait loci in rat and mouse has been extremely successful in identifying chromosomal regions associated with human disease-related phenotypes. However, identifying the specific phenotype-causing DNA sequence variations within a quantitative trait locus has been much more difficult. The recent availability of genomic sequence from several mouse inbred strains (including C57BL/6J, 129X1/SvJ, 129S1/SvImJ, A/J, and DBA/2J) has made it possible to catalog DNA sequence differences within a quantitative trait locus derived from crosses between these strains. However, even for well-defined quantitative trait loci (<10 Mb) the identification of candidate functional DNA sequence changes remains challenging due to the high density of sequence variation between strains. DESCRIPTION: To help identify functional DNA sequence variations within quantitative trait loci we have used the Ensembl annotated genome sequence to compile a database of mouse single nucleotide polymorphisms (SNPs) that are predicted to cause missense, nonsense, frameshift, or splice site mutations (available at ). For missense mutations we have used the PolyPhen and PANTHER algorithms to predict whether amino acid changes are likely to disrupt protein function. CONCLUSION: We have developed a database of mouse SNPs predicted to cause missense, nonsense, frameshift, and splice-site mutations. Our analysis revealed that 20% and 14% of missense SNPs are likely to be deleterious according to PolyPhen and PANTHER, respectively, and 6% are considered deleterious by both algorithms. The database also provides gene expression and functional annotations from the Symatlas, Gene Ontology, and OMIM databases to further assess candidate phenotype-causing mutations. To demonstrate its utility, we show that Mouse SNP Miner successfully finds a previously identified candidate SNP in the taste receptor, Tas1r3, that underlies sucrose preference in the C57BL/6J strain. We also use Mouse SNP Miner to derive a list of candidate phenotype-causing mutations within a previously uncharacterized QTL for response to morphine in the 129/Sv strain

Whitefly (Bemisia tabaci) genome project: analysis of sequenced clones from egg, instar, and adult (viruliferous and non-viruliferous) cDNA libraries

BACKGROUND: The past three decades have witnessed a dramatic increase in interest in the whitefly Bemisia tabaci, owing to its nature as a taxonomically cryptic species, the damage it causes to a large number of herbaceous plants because of its specialized feeding in the phloem, and to its ability to serve as a vector of plant viruses. Among the most important plant viruses to be transmitted by B. tabaci are those in the genus Begomovirus (family, Geminiviridae). Surprisingly, little is known about the genome of this whitefly. The haploid genome size for male B. tabaci has been estimated to be approximately one billion bp by flow cytometry analysis, about five times the size of the fruitfly Drosophila melanogaster. The genes involved in whitefly development, in host range plasticity, and in begomovirus vector specificity and competency, are unknown. RESULTS: To address this general shortage of genomic sequence information, we have constructed three cDNA libraries from non-viruliferous whiteflies (eggs, immature instars, and adults) and two from adult insects that fed on tomato plants infected by two geminiviruses: Tomato yellow leaf curl virus (TYLCV) and Tomato mottle virus (ToMoV). In total, the sequence of 18,976 clones was determined. After quality control, and removal of 5,542 clones of mitochondrial origin 9,110 sequences remained which included 3,843 singletons and 1,017 contigs. Comparisons with public databases indicated that the libraries contained genes involved in cellular and developmental processes. In addition, approximately 1,000 bases aligned with the genome of the B. tabaci endosymbiotic bacterium Candidatus Portiera aleyrodidarum, originating primarily from the egg and instar libraries. Apart from the mitochondrial sequences, the longest and most abundant sequence encodes vitellogenin, which originated from whitefly adult libraries, indicating that much of the gene expression in this insect is directed toward the production of eggs. CONCLUSION: This is the first functional genomics project involving a hemipteran (Homopteran) insect from the subtropics/tropics. The B. tabaci sequence database now provides an important tool to initiate identification of whitefly genes involved in development, behaviour, and B. tabaci-mediated begomovirus transmission

The Critical Role of Chemokine (C–C Motif) Receptor 2-Positive Monocytes in Autoimmune Cholangitis

The therapy of primary biliary cholangitis (PBC) has lagged behind other autoimmune diseases despite significant improvements in our understanding of both immunological and molecular events that lead to loss of tolerance to the E2 component of pyruvate dehydrogenase, the immunodominant autoepitope of PBC. It is well known that Ly6Chi monocytes are innate immune cells infiltrating inflammatory sites that are dependent on the expression of C–C motif chemokine receptor 2 (CCR2) for emigration from bone marrow. Importantly, humans with PBC have a circulating monocyte pro-inflammatory phenotype with macrophage accumulation in portal tracts. We have taken advantage of an inducible chemical xenobiotic model of PBC and recapitulated the massive infiltration of monocytes to portal areas. To determine the clinical significance, we immunized both CCR2-deficient mice and controls with 2OA-BSA and noted that CCR2 deficiency is protective for the development of autoimmune cholangitis. Importantly, because of the therapeutic potential, we focused on inhibiting monocyte infiltration through the use of cenicriviroc (CVC), a dual chemokine receptor CCR2/CCR5 antagonist shown to be safe in human trials. Importantly, treatment with CVC resulted in amelioration of all aspects of disease severity including serum total bile acids, histological severity score, and fibrosis stage. In conclusion, our results indicate a major role for Ly6Chi monocytes and for CCR2 in PBC pathogenesis and suggest that inhibition of this axis by CVC should be explored in humans through the use of clinical trials

The genetic background effect on domesticated species: a mouse evolutionary perspective

Laboratory mouse strains are known for their large phenotypic diversity and serve as a primary mammalian model in genotype-phenotype association studies. One possible attempt to understand the reason for this diversity could be addressed by careful investigation of the unique evolutionary history of their wild-derived founders and the consequence that it may have on the genetic makeup of the laboratory mouse strains during the history of human fancy breeding. This review will summarize recently published literature that endeavors to unravel the genetic background of laboratory mouse strains, as well as give new insights into novel evolutionary approaches. I will explain basic concepts of molecular evolution and the reason why it is important in order to infer function even among closely related wild and domesticated species. I will also discuss future frontiers in the field and how newly emerging sequencing technologies could help us to better understand the relationship between genotype and phenotype. KEYWORDS: domesticated species, wild species, laboratory mouse strains, evolution, natural selection, population genetics, speciation, genotype-phenotype map LABORATORY MOUSE STRAINS IN MEDICAL RESEARCH Although laboratory mouse strains all belong to the same species, Mus musculus, hundreds of laboratory mouse strains provide a collection of models owing to their differences in physiological, clinical, morphological, and behavioral traits THE GENETIC BACKGROUND OF LABORATORY MOUSE STRAINS Laboratory mouse strains are believed to have emerged from the human fancy breeding history of three wild-derived subspecies (M. m. domesticus, M. m. musculus, and M. m. casteneus) We can distinguish between two predominant models that attempt to explain the genetic background of laboratory mouse strains ( Reuveni: The Evolution Background of Domesticated Species TheScientificWorldJOURNAL (2011) 11, 429-436 431 The two models are discussed in the following three independent studies. Wade et al.[20] were the first to validate a previous hypothesis of the mosaic model casteneus). The discordance between the last two studies is notable and could be affected by misjudgment of prior assumptions of the hypothetic number of subspecies origin. The fact that 20% of the genome could not be assigned to any of the wild-derived ancestors could be due to the following possibilities: (1) a substantial fraction of the ancestry of classical strains is unsampled, thus the level of genetic diversity within a subspecies population is postulated to be very large; (2) a possible contribution from another M. musculus subspecies. NATURAL SELECTION AND THE EVOLUTIONARY HISTORY OF WILD MICE In order to better understand the genetic makeup of the laboratory mouse strains, it is essential to get an insight into the evolutionary history of their founder origin. As previously explained in the text, the M. musculus subspecies are known to inhabit naturally across three continents with a stringent barrier to gene flow for the last 1 million years (allopatric species) Reuveni: The Evolution Background of Domesticated Species NOVEL METHOD TO UNRAVEL THE GENESIS OF LABORATORY MOUSE STRAINS Building on the same dataset of Frazer et al. [37] developed a novel unbiased method to estimate the number of subspecies founders, excluding prior assumption of ancestral origin. In addition, a pool of genes that may have been under relaxed selective constraints in the ancestral population was proposed. The basic assumption in this study was that a comparison of coding regions between laboratory strains is sufficient to understand the phyletic origin without any clear statement of the correct assignments to the subspecies origin. The approach described in the paper made two prior hypotheses regarding the expected polymorphic spectrum of the laboratory mouse: (1) multifounder origin should be represented by a bimodal distribution when comparing the genetic distance of neutral coding mutations and (2) the d N /d S distribution between haplotypes of laboratory strains should keep the molecular signature of its founder origin. The strength behind this approach is that it reduces the likelihood of making a faulty assignment of haplotypes due to evolutionary or sampling effects. Additionally, but more importantly, it allows the drawing of some conclusions regarding the degree of Reuveni: The Evolution Background of Domesticated Species TheScientificWorldJOURNAL (2011) 11, 429-436 433 fitness of the genome (or the proportion of mutations that survived selective removal), therefore, to get a more reliable prediction of candidate beneficial mutations. The methods described by Frazer et al.[18] and Yang et al.[21] assigned laboratory mouse haplotypes to their wild-derived ancestors using the latter as the frame sequence. In many cases, the sequenced haplotypes of the wild-derived strains contain large genetic variability that cannot be observed in the laboratory haplotype. For example, individuals from the same population may differ extremely between loci due to the consequence of positive and purifying selection or due to a large genetic drift. Such evolutionary effects can result in one of the following possibilities: (1) the laboratory haplotype is not appropriately classified or (2) the laboratory haplotype is classified as &quot;of an unknown genetic background&quot;. Thus, each one of the two possibilities will fail to state the correct ancestral origin. There are few reasons to believe that the evolutionary approach is less vulnerable to sampling errors. Reuveni et al.[37] demonstrated that pair-wise comparison of the d N /d S distribution is similar between the three subspecies for the same gene set and validates the expectation that in a genome-wide manner, natural selection will have, on average, the same impact among each one of the subspecies. However when two rodents from the same subspecies population are examined, a significant up-shift in the d N /d S distribution was observed, suggesting that the efficacy of natural selection is proportional to the time since the branching event. Since natural selection may have a variable effect on different genes, gene-bygene comparison could lead to a faulty statement for the nature of each one of the haplotype origins. However, careful examination of the cumulative d N /d S distribution in a genome-wide manner may eliminate errors that could occur due to a single gene affair and support evidence of a common mutability space that is shared between different subspecies. The first interesting finding, and in concordance with their expectations, was that the comparison of 2,000 coding genes of laboratory mouse strains revealed that the d N /d S distribution was extremely similar to the one that was observed between different subspecies, but different from the within rodent comparison. This was the first confirmation to the assumption that laboratory mouse strains have inherited genetic materials from several mouse subspecies. In additional analysis, but this time using neutral (synonymous) polymorphisms to estimate the amount of genetic distance between genes, Reuveni et al. DOMESTICATED SPECIES AND NEW FRONTIERS IN SEQUENCING TECHNIQUES The cross-continental immigration history of humans was followed by the domestication of a variety of species, including plants, yeast, and animals that were bred in order to improve agricultural crops or as companion pets Reuveni: The Evolution Background of Domesticated Species 434 interaction. Due to their unusual genetic makeup and as a result of their unusual breeding, domesticated strains provide us with a unique resource to address these questions. In addition to their ability to exhibit unusual phenotypes, domesticated species can help us to understand the mechanism of reproductive isolation and speciation Up until recent years, old and highly costly sequencing technologies allowed the full genomic profile of only a restricted number of species to be obtained. This allowed us to study the evolution of the genome only between distantly related organisms, leaving our understanding of its mechanism within closely related species very vague. However due to the reduction in the cost on the one hand and better accuracy of the read calls on the other CONCLUSIONS Unraveling the genetic background of domesticated animals is a great challenge and one step forward in our understanding of the evolution of selected traits. Being the most-studied mammalian species, the laboratory mouse strains provide an undeniable source of phenotypes that may help us to get a better comprehensive view of the link between the genotype and the phenotype. In this review, I have described a novel approach to unravel the genetic architecture of domesticated animals by using mouse evolution as a probe. From an evolutionary perspective, I have explained that natural selection was particularly effective on the removal of deleterious mutations from the ancestral wild-mice populations. The evidence that many of the polymorphisms are fixed in the laboratory mouse strains confirms the polyphyletic origin of those animals and facilitates the ability to do fine mapping of quantitative trait loci (QTL) underlying complex traits ACKNOWLEDGMENT

A Novel Multi-Scale Modeling Approach to Infer Whole Genome Divergence

We propose a novel and simple approach to elucidate genomic patterns of divergence using principal component analysis (PCA). We applied this methodology to the metric space generated by M. musculus genome-wide SNPs. Distance profiles were computed between M. musculus and its closely related species, M. spretus , which was used as external reference. While the speciation dynamics were apparent in the first principal component, the within M. musculus differentiation dimensions gave rise to three minor components. We were unable to obtain a clear divergence signature discriminating laboratory strains, suggesting a stronger effect of genetic drift. These results were at odds with wild strains which exhibit defined deterministic signals of divergence. Finally, we were able to rank novel and previously known genes according to their likelihood to be under selective pressure. In conclusion, we posit PCA as a robust methodology to unravel diverging DNA regions without any a priori forcing