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PubMed1982

Expected frequencies of codon use as a function of mutation rates and codon fitnesses.

A method is shown to determine the expected pattern of codon use for any given set of mutation rates between nucleotides and any set of fitnesses for the codons. If it is assumed that mutations to stop codons are lethal then those codons which can mutate in one step to a stop codon tend to be used less frequently. This tendency is however, a very small one and is not likely to be observable within a single gene. Nor is it necessarily a general tendency. For example, the leucine pretermination codons may be used preferentially when mutations to proline are deleterious. It is shown that different mutation rates (eg: transitions occurring more frequently than transversions) may have as large an effect on codon usage as would strong selection for particular codons. For the model presented, an increase in the rate of transitions strongly decreases the expected frequency of UGG and CRR codons. Other codes are moderately affected by such a change in the mutation rates. Many other models can be examined using this method.

Amino Acids↗

PubMed2006

The automation of Nested Clade Phylogeographic Analysis.

UNLABELLED: ANeCA is a fully automated implementation of Nested Clade Phylogeographic Analysis. This was originally developed by Templeton and colleagues, and has been used to infer, from the pattern of gene sequence polymorphisms in a geographically structured population, the historical demographic processes that have shaped its evolution. Until now it has been necessary to perform large parts of the procedure manually. We provide a program that will take data in Nexus sequential format, and directly output a set of inferences. The software also includes TCS v1.18 and GeoDis v2.2 as part of automation. AVAILABILITY: The software is available free of charge from http://www.rubic.rdg.ac.uk/~mahesh/software.html. The program is written in Java and requires the Java 1.4 Runtime Environment (or later) to run. The source code is included in the package, and includes the source from TCS and GeoDis. ANeCA, TCS and GeoDis are released under the GNU General Public License.

Algorithms↗

PubMed2006

Rate of promoter class turn-over in yeast evolution.

BACKGROUND: Phylogenetic conservation at the DNA level is routinely used as evidence of molecular function, under the assumption that locations and sequences of functional DNA segments remain invariant in evolution. In particular, short DNA segments participating in initiation and regulation of transcription are often conserved between related species. However, transcription of a gene can evolve, and this evolution may involve changes of even such conservative DNA segments. Genes of yeast Saccharomyces have promoters of two classes, class 1 (TATA-containing) and class 2 (non-TATA-containing). RESULTS: Comparison of upstream non-coding regions of orthologous genes from the five species of Saccharomyces sensu stricto group shows that among 212 genes which very likely have class 1 promoters in S. cerevisiae, 17 probably have class 2 promoters in one or more other species. Conversely, among 322 genes which very likely have class 2 promoters in S. cerevisiae, 44 probably have class 1 promoters in one or more other species. Also, for at least 2 genes from the set of 212 S. cerevisiae genes with class 1 promoters, the locations of the TATA consensus sequences are substantially different between the species. CONCLUSION: Our results indicate that, in the course of yeast evolution, a promoter switches its class with the probability at least approximately 0.1 per time required for the accumulation of one nucleotide substitution at a non-coding site. Thus, key sequences involved in initiation of transcription evolve with substantial rates in yeast.

Base Sequence↗

PubMedDate not supplied

The minimal cellular genome of mycoplasma.

The mycoplasmas are the smallest and simplest self-replicating organisms, being built of a plasma membrane, ribosomes, and a circular double-stranded DNA molecule-the typical prokaryotic genome. The idea of using mycoplasmas as models for defining in molecular terms the entire machinery of a living cell was raised by Morowitz in 1984. The goal has been to prove the dogma of the completeness of molecular biology, that is, that the logic of life is finite, relatively simple and subject to full exploration. The recent complete sequencing of the genome of the human pathogen Mycoplasma genitalium brings us much closer to achieving this goal. The M. genitalium genome is only 580 kb long and contains only 470 predicted coding sequences(genes), as compared with 1727 in Haemophilus influenzae and about 4000 in E. coli. Thus, M. genitalium is apparently the simplest organism capable of independent life with a minimal set of genes. The drastic economization in genetic information must be associated with the parasitic mode of life of the mycoplasmas. Mycoplasmas evolved by reductive evolution from Gram-positive bacteria with low G + C genomes. During evolution the mycoplasmas have lost the cell wall and many biosynthetic systems involved in synthesis of macromolecule building blocks provided by their host. Thus, the M. genitalium genome carries only one gene involved in amino acid biosynthesis, and very few genes for vitamin and nucleic acid precursors; the lack of genes involved in fatty acid biosynthesis, leads to dependence on exogenous fatty acids, enabling the introduction of controlled variations in membrane acyl chains and the use of mycoplasmas as models in studying membrane fluidity. Moreover, the dependence of mycoplasmas on exogenous cholesterol for growth was exploited to show the role of cholesterol as a buffer of membrane fluidity. The mycoplasma genome carries the minimal set of energy metabolism genes, being content with a restricted supply of ATP needed for their parasitic mode of life. Being limited by a single permeability barrier enabled the saving of a considerable number of transport system genes. Nevertheless, these minimal organisms were shown to carry all the essential genes needed for DNA replication, transcription and translation, but even here gene saving is expressed in a minimal number of rRNA and tRNA genes. A genomic price had been paid to maintain parasitism, so that a significant number of mycoplasmal genes is devoted to adhesins, attachment organelles and variable membrane surface antigens directed towards evasion of the host immune system.

Genome, Bacterial↗

PubMed2001

The evolutionary history of chromosomal super-integrons provides an ancestry for multiresistant integrons.

Integrons are genetic elements that acquire and exchange exogenous DNA, known as gene cassettes, by a site-specific recombination mechanism. Characterized gene cassettes consist of a target recombination sequence (attC site) usually associated with a single open reading frame coding for an antibiotic resistance determinant. The affiliation of multiresistant integrons (MRIs), which contain various combinations of antibiotic resistance gene cassettes, with transferable elements underlies the rapid evolution of multidrug resistance among diverse Gram-negative bacteria. Yet the origin of MRIs remains unknown. Recently, a chromosomal super-integron (SI) harboring hundreds of cassettes was identified in the Vibrio cholerae genome. Here, we demonstrate that the activity of its associated integrase is identical to that of the MRI integrase, IntI1. We have also identified equivalent integron superstructures in nine distinct genera throughout the gamma-proteobacterial radiation. Phylogenetic analysis revealed that the evolutionary history of the system paralleled that of the radiation, indicating that integrons are ancient structures. The attC sites of the 63 antibiotic-resistance gene cassettes identified thus far in MRIs are highly variable. Strikingly, one-fifth of these were virtually identical to the highly related yet species-specific attC sites of the SIs described here. Furthermore, antimicrobial resistance homologues were identified among the thousands of genes entrapped by these SIs. Because the gene cassettes of SIs are substrates for MRIs, these data identify SIs as the source of contemporary MRIs and their cassettes. However, our demonstration of the metabolic functions, beyond antibiotic resistance and virulence, of three distinct SI gene cassettes indicates that integrons function as a general gene-capture system for bacterial innovation.

Alteromonas↗

PubMed1990

Genetic analysis of a vital mammalian housekeeping locus using CHO cells that express a transfected mutant allele.

We describe a novel approach for the isolation of null mutations in a vital Chinese hamster ovary (CHO) cell housekeeping gene. Our experimental strategy required introduction of an expressible DNA clone encoding a recessive emetine-resistance allele of ribosomal protein S14 into wild-type CHO cells. Transgene heterozygote (TGH) cell lines, which harbor multiple emetine-resistance S14 transgenes, survive mutations that inactivate the CHO RPS14 locus by virtue of the transgenes' biological function. Null mutations in RPS14 yield TGH clones that display the transgene's drug-resistance phenotype. A large collection of emetine-resistant clones was isolated from one TGH cell line and shown to consist of three types of S14 mutations: (1) nonsense null mutations in the RPS14 protein coding sequence; (2) missense null mutations that affect S14 amino acid residues that have been conserved stringently during eukaryotic evolution; and (3) a recurrent missense mutation that results in a new, functional RPS14 emetine-resistance allele.

Amino Acid Sequence↗

PubMed1998

Chromosomal fragility may be indicative of altered higher-order DNA organization as the underlying genetic diathesis in complex neurobehavioral disorders.

Preliminary observations concerning increased chromosomal fragility in association with behavioural disorders in humans allow an opportunity to suggest a cohesive theory regarding the possible importance of higher-order DNA modifications in the coordination of gene function in brain evolution and during development. Visible or submicroscopic acentric chromosomal fragments are formed as an accompaniment to chromosomal breakage and are associated with sequence amplification. During genomic reintegration of extrachromosomally amplified repeat sequence elements, functional consequences could include unequal crossing over with gain-of-function, and/or deletion with loss-of-function. This process could result in regulatory changes in gene function in association with normal coding regions, since fragile sites appear to be located at or near upstream DNaseI-hypersensitive areas. Earlier research on chromosomal breakage in relation to transposon behaviour in maize has set a precedent by which many elements in a network could be coordinately controlled, a principle which may allow transcriptional control over multiple areas in the genome simultaneously. The hypothesis proposed in this paper implies that a small number of fundamental higher-order changes may be responsible for influencing a wide range of genetic alterations leading to complex phenotypes, sometimes segregating as distinct entities within pedigrees, or alternatively, and perhaps more commonly, presenting with several overlapping phenotypes in some other families. Studying only pure multiplex families in psychiatric genetics may not be sufficient for an understanding of the underlying genetic diathesis in this group of disorders. Validation of the fragile site hypothesis for complex neurobehavioural disorders may offer additional avenues for gene therapy based either on preferential integration of exogenous DNA at fragile sites, or utilizing the acentric fragments to modify sequence amplification extrachromosomally.

Chromosome Breakage↗

PubMed1992

Behavioural endocrinology and reproduction: an evolutionary perspective.

It is a fact that those interested in immediate causation tend to be unaware of the great advances in evolutionary biology. Similarly, most scientists interested in ecological and evolutionary questions ignore advances in neurobiology and molecular biology. Quite simply, 'reductionists see little to be gained from holistic studies, and whole organism biologists do not recognize the value of molecular analysis' (Prosser 1986). This philosophical gap and lack of communication between molecular and physiological biologists with organismal and evolutionary biologists makes it difficult to be a generalist. Yet if we are to understand past, present, and perhaps even future behaviour, we must study how the different levels of biological organization are integrated. If done with foresight, it can lead to new discoveries not only in evolution and ecology, but also in physiology and even molecular biology. One of the first things we are impressed by is the great variety of animals, particularly their behaviours and their physiologies. With so many differences, are there any generalities? With the establishment of evolutionary theory, evidence that there is 'unity in diversity' has come with discoveries of common anatomical features, the cell cycle, conservation of intermediary metabolism, and the genetic code, to name but a few. While in vertebrates there appears to be a conservation of the neural circuits underlying sex behaviour, it is still too early to state the extent to which this concept can be extended to the hormonal mechanisms underlying behaviour. This chapter has documented how some widely-held assumptions are generalities only in a very restricted sense. I have tried to show how much of our conceptual understanding of the behavioural endocrinology stems from extensive studies on relatively few species. According to (Beach 1979), there are '... two cardinal rules that should govern not only the construction of animal models for human behaviour, but for all interspecific comparisons regardless of the behaviour and the species involved. The first rule is that meaningful comparisons are based not upon the formal characteristics of behaviour, but upon its causal mechanisms and functional outcomes.... The second rule is that the validity of interspecific generalization cannot exceed the reliability of intraspecific analysis. Significant comparison of a particular type of behaviour in two different species is impossible unless and until the behaviour has been adequately analyzed in each species by itself.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2000

Assessment of genotype and molecular evolution of hepatitis C virus in formalin-fixed paraffin-embedded liver tissue from patients with chronic hepatitis C virus infection.

Drawbacks of hepatitis C virus (HCV) RNA detection in paraffin-embedded liver tissue have satisfactorily been solved by RT-PCR amplification of the 5'non-coding region (5'NCR). However, detection of this highly conserved region does not provide information on epidemiological or pathogenetic aspects of HCV infection. This study explores whether other functionally important genetic regions of HCV, such as the hypervariable region 1 (HVR-1) and the interferon sensitivity-determining region (ISDR), can be retrieved from paraffin-embedded liver specimens by RT-PCR, and whether the amplified material is suitable for further molecular analyses. RT-PCR amplification of 5'NCR, HVR-1, and ISDR was assessed in RNA extracted from 50 formalin-fixed, paraffin-embedded liver specimens, including 23 needle liver biopsies (11 from patients with non-A, non-B chronic hepatitis diagnosed between 1971 and 1985, 8 from subjects with normal liver histology and 4 from sequential biopsies from a patient with HCV recurrence after liver transplantation), and 27 liver explants from patients undergoing transplantation between 1988 and 1996 (16 with HCV-related cirrhosis and 11 with other disorders). The 5'NCR was successfully amplified in 8 of 11 (73%) non-A, non-B chronic hepatitis biopsies and in all of the specimens from patients with serological documentation of HCV infection. There were no false-positive results. HCV genotype was identified by RFLP analysis of the 5'NCR in the 13 cases analyzed. HVR-1 and ISDR were amplified in 24 of 28 (86%) samples, which were positive for the 5'NCR. Efficient amplification was inversely related to the time of storage. The evolutionary changes of HVR-1 and ISDR were successfully analyzed by direct sequencing of amplificates from the explanted liver and from the sequential liver biopsies in a patient with HCV infection recurrence after transplantation. These observations indicate that paraffin-embedded liver tissue, even when stored for more than 20 years, is appropriate for advanced studies on the molecular biology of HCV.

Amino Acid Sequence↗

PubMed1987

Evolution of genes for allelic and isotypic forms of immunoglobulin kappa chains and of the genes for T-cell receptor beta chains in rabbits.

New insights into the evolution of the families of genes encoding immunoglobulins and T-cell receptors of rabbits (Oryctolagus cuniculus) have come from molecular genetic studies. In contrast to human and mouse, rabbits were shown to have two genes for the constant region of immunoglobulin light chains (C kappa 1 and C kappa 2 isotypes) and complex allelic variants of K1 (allotypes). Although K1 allotype protein sequences differed at up to 41% of the amino acid positions, 3' untranslated, 5', and 3' flanking regions were conserved, and in the coding regions 78-80% of the codons with differences had replacement changes. Proportions of silent changes and changes in noncoding regions were comparable. Thus, in spite of their markedly different protein sequences, the K1b4, b5, and b9 allotypes appeared to be products of allelic genes. Molecular genetic analyses suggested that they may have undergone rapid divergence after an ancestral K2-like gene duplicated. Some rabbits were found to have two similar T-cell receptor C beta genes as do humans and many strains of mice, but others appeared to have three different C beta. In addition, we found allotypic forms of C beta. Some of the C beta allotypic differences occurred at positions where analogous C kappa allotypic differences were found. We also found V beta in mouse and human that were more similar to rabbit V beta than closely linked rabbit genes were to each other. This contrasts with rabbit immunoglobulin VH gene sequences that reflect concerted evolution. The data suggested that T-cell receptor V beta genes duplicated prior to mammalian radiation.

Alleles↗

PubMed2002

Approaches to prokaryotic biodiversity: a population genetics perspective.

The study of prokaryotic diversity has blossomed during the last 10-15 years as a result of the introduction of molecular identification, mostly based on direct 16S rRNA gene polymerase chain reaction (PCR) amplification and sequencing from natural samples. A large amount of information exists about the diversity of this specific gene. However, data from the field of bacterial population genetics and genomics make questionable the value of information regarding just one gene. Even if we accept 16S rRNA genes as useful for species identification, intraspecific variation in bacteria is so high that species catalogues are often of little value. The gene pools represented by an operational species are yet impossible to predict. On the other hand, adaptive features in prokaryotes are often coded in gene clusters (genomic islands) that can be cloned directly from the environment, sequenced and even expressed in a surrogate host. Thus, the study of the environmental genome or metagenome appears as an alternative that could eventually lead to a more realistic understanding of prokaryotic biodiversity, provide biotechnology with new tools and maybe even contribute to develop a model of prokaryotic evolution.

Biological Evolution↗

PubMed1996

The three human cytochrome P450 lanosterol 14 alpha-demethylase (CYP51) genes reside on chromosomes 3, 7, and 13: structure of the two retrotransposed pseudogenes, association with a line-1 element, and evolution of the human CYP51 family.

The three human lanosterol 14 alpha-demethylase (CYP51) genes have been mapped to human chromosomes 3, 7, and 13 using a polychromosomal somatic cell hybrid panel. Two of the genes have been cloned from human chromosome 3-specific (CYP51P1) or from human chromosome 13-containing (CYP51P2) cell hybrids. Both were found to be processed pseudogenes, the first reported in the cytochrome P450 (CYP) gene superfamily. The functional CYP51 gene resides on human chromosome 7. CYP51P1 is 96.5% identical to the human CYP51 coding sequence and is not interrupted with introns but has six in-frame stop codons resulting from point mutations. The intronless CYP51P2 gene is 97.2% identical to the CYP51 cDNA coding region. It has a 1-bp insertion leading to a change of reading frame after codon 9 and a stop codon after amino acid 81. In addition, the CYP51P2 sequence is interrupted with a 5' truncated 131-bp LINE-1 element after nucleotide 606. The element belongs to the youngest LINE subfamily Sb and is 98.2% identical to the LINE-1 element expressed in human teratocarcinoma cells. CYP51 processed pseudogenes are the only known examples of the reverse flow of genetic information during evolution of the large (more than 480 genes) CYP superfamily, suggesting expression in the germ line and a housekeeping function of the lanosterol 14 alpha-demethylase gene. CYP51 pseudogenes evolved by two independent reverse transcription events of the human CYP51 mRNA approximately 9.5 MYR (CYP51P2) and approximately 11.7 MYR (CYP51P1) ago and were inactivated soon after the insertion. The truncated L1 element was inserted into CYP51P2 approximately 6 MYR ago.

Amino Acid Sequence↗

PubMed2004

From "junk" to gene: curriculum vitae of a primate receptor isoform gene.

Exonization of Alu retroposons awakens public opinion, particularly when causing genetic diseases. However, often neglected, alternative "Alu-exons" also carry the potential to greatly enhance genetic diversity by increasing the transcriptome of primates chiefly via alternative splicing.Here, we report a 5' exon generated from one of the two alternative transcripts in human tumor necrosis factor receptor gene type 2 (p75TNFR) that contains an ancient Alu-SINE, which provides an alternative N-terminal protein-coding domain. We follow the primate evolution over the past 63 million years to reconstruct the key events that gave rise to a novel receptor isoform. The Alu integration and start codon formation occurred between 58 and 40 million years ago (MYA) in the common ancestor of anthropoid primates. Yet a functional gene product could not be generated until a novel splice site and an open reading frame were introduced between 40 and 25 MYA on the catarrhine lineage (Old World monkeys including apes).

Animals↗

PubMed2001

Phylogenetic network for European mtDNA.

The sequence in the first hypervariable segment (HVS-I) of the control region has been used as a source of evolutionary information in most phylogenetic analyses of mtDNA. Population genetic inference would benefit from a better understanding of the variation in the mtDNA coding region, but, thus far, complete mtDNA sequences have been rare. We determined the nucleotide sequence in the coding region of mtDNA from 121 Finns, by conformation-sensitive gel electrophoresis and subsequent sequencing and by direct sequencing of the D loop. Furthermore, 71 sequences from our previous reports were included, so that the samples represented all the mtDNA haplogroups present in the Finnish population. We found a total of 297 variable sites in the coding region, which allowed the compilation of unambiguous phylogenetic networks. The D loop harbored 104 variable sites, and, in most cases, these could be localized within the coding-region networks, without discrepancies. Interestingly, many homoplasies were detected in the coding region. Nucleotide variation in the rRNA and tRNA genes was 6%, and that in the third nucleotide positions of structural genes amounted to 22% of that in the HVS-I. The complete networks enabled the relationships between the mtDNA haplogroups to be analyzed. Phylogenetic networks based on the entire coding-region sequence in mtDNA provide a rich source for further population genetic studies, and complete sequences make it easier to differentiate between disease-causing mutations and rare polymorphisms.

Codon↗

PubMed1999

Cytochrome b evolution in birds and mammals: an evaluation of the avian constraint hypothesis.

Patterns of molecular evolution in birds have long been considered anomalous. Compared with other vertebrates, birds have reduced levels of genetic divergence between groups of similar taxonomic ranks for a variety of nuclear and mitochondrial markers. This observation led to the avian constraint hypothesis, which identifies increased functional constraint on avian proteins as the cause for the reduction in genetic divergence. Subsequent investigations provided additional support for the avian constraint hypothesis when rates of molecular evolution were found to be slower in birds than in mammals in a variety of independent calibrations. It is possible to test the avian constraint hypothesis as an explanation for this avian slowdown by comparing DNA sequence data from protein-coding regions in birds and homologous regions in mammals. The increased selective constraints should lead to a reduction in the proportion of amino acid replacement substitutions. To test for such a decrease, we calculated the numbers of amino acid replacement substitutions per replacement site (dN) and silent substitutions per silent site (dS) for the complete mitochondrial cytochrome b gene using 38 avian and 43 mammalian comparisons that were phylogenetically independent. We find that dN/dS is significantly smaller in birds than in mammals. This difference cannot be explained by differences in codon bias affecting dS values. We suggest that the avian slowdown can be explained, at least in part, by a decreased tolerance for amino acid substitutions in avian species relative to mammalian species.

Animals↗

PubMed2003

Analysis of genome plasticity in pathogenic and commensal Escherichia coli isolates by use of DNA arrays.

Genomes of prokaryotes differ significantly in size and DNA composition. Escherichia coli is considered a model organism to analyze the processes involved in bacterial genome evolution, as the species comprises numerous pathogenic and commensal variants. Pathogenic and nonpathogenic E. coli strains differ in the presence and absence of additional DNA elements contributing to specific virulence traits and also in the presence and absence of additional genetic information. To analyze the genetic diversity of pathogenic and commensal E. coli isolates, a whole-genome approach was applied. Using DNA arrays, the presence of all translatable open reading frames (ORFs) of nonpathogenic E. coli K-12 strain MG1655 was investigated in 26 E. coli isolates, including various extraintestinal and intestinal pathogenic E. coli isolates, 3 pathogenicity island deletion mutants, and commensal and laboratory strains. Additionally, the presence of virulence-associated genes of E. coli was determined using a DNA "pathoarray" developed in our laboratory. The frequency and distributional pattern of genomic variations vary widely in different E. coli strains. Up to 10% of the E. coli K-12-specific ORFs were not detectable in the genomes of the different strains. DNA sequences described for extraintestinal or intestinal pathogenic E. coli are more frequently detectable in isolates of the same origin than in other pathotypes. Several genes coding for virulence or fitness factors are also present in commensal E. coli isolates. Based on these results, the conserved E. coli core genome is estimated to consist of at least 3,100 translatable ORFs. The absence of K-12-specific ORFs was detectable in all chromosomal regions. These data demonstrate the great genome heterogeneity and genetic diversity among E. coli strains and underline the fact that both the acquisition and deletion of DNA elements are important processes involved in the evolution of prokaryotes.

Electrophoresis, Gel, Pulsed-Field↗

PubMed1999

Chromosomal fragility may be indicative of altered higher-order DNA organization as the underlying genetic diathesis in complex neurobehavioural disorders.

Preliminary observations concerning increased chromosomal fragility in association with certain behavioural disorders in humans allow an opportunity to suggest a cohesive theory regarding the possible importance of higher-order DNA modification in the coordination of gene function in brain evolution and during development. Visible or submicroscopic acentric chromosomal fragments are formed as an accompaniment to chromosomal breakage and are associated with sequence amplification. During genomic reintegration of such extra chromosomally amplified repeat sequence elements, functional consequences could include unequal crossing over with gain-of-function, and/or deletion with loss-of-function. This process could result in regulatory changes in gene function in association with normal coding regions, since fragile sites appear to be located at or near upstream DNase-I hypersensitive areas. Earlier research on chromosomal breakage in relation to transposon behaviour in maize has set a precedent by which many elements in a network could be coordinately controlled, a principle which may allow transcriptional control over multiple areas in the genome simultaneously. The hypothesis proposed in this paper implies that a small number of fundamental higher order changes may be responsible for influencing a wide range of genetic alterations leading to complex phenotypes, sometimes segregating as distinct entities within pedigrees, or alternatively, and perhaps more commonly, presenting with several overlapping phenotypes in some other families. Current emphasis on the investigation of only pure multiplex families in psychiatric genetics may assist with identification of a number of discrete behaviour-modifying genes, but may not be sufficient for an understanding of the broad underlying genetic diathesis in these, and perhaps other 'multifactorial type' disorders. Validation of a role for altered fragile site expression and the molecular consequences thereof as proposed in this paper may offer additional avenues for gene therapy based either on preferential integration of exogenous DNA at fragile sites, or utilizing the acentric fragments formed during chromosome breakage to modify sequence amplification extrachromosomally.

Animals↗

PubMed2004

Quantitative genetic variation: a post-modern view.

It has become commonplace to map individual quantitative trait loci (QTL) in experimental organisms; the means (line-crosses and dense maps of markers) and motivation (the close relationship between continuous physiological traits and common, complex diseases) are self-evident. Progress in mapping human QTL has been more gradual, an inevitable consequence of genetic mapping in a natural population setting. The common objective of these studies has been to understand the molecular mechanisms underlying individual QTL. Recent theoretical and practical advances shift this focus to a more comprehensive or genomic perspective on quantitative variation. Fisher's infinitesimal model of adaptive evolution, which satisfied quantitative geneticists for over 50 years, has been modified in the light of data from QTL mapping experiments in plants and animals. The resulting exponential model provides a pleasing empirical fit to the distribution of QTL effect sizes, predicts that a large amount of quantitative variation will be explained by a limited number of genes and suggests a new mathematical framework for linkage mapping. Molecular analysis of QTL suggests that coding variants (e.g. allozymes) underlie a fraction of quantitative variation and that variants that affect gene expression (expression QTL, eQTL) have a substantial role. This is supported by genomic experiments that combine expression profiling with classical genetic mapping approaches to reveal a remarkable wealth of quantitative heritable variation in the transcriptome and that cis-and trans-acting regulatory factors are organized in networks reflecting pleiotropy. It is hoped that these advances will enhance our understanding of the genetic basis of complex inherited diseases.

Animals↗