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Gene Mapping

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Genetics of the Mouse

Abstract

Now that the sequence of the mouse genome is completely known, the position of any gene of the species can be accurately and rapidly established by searching the appropriate database. In this context, a chapter devoted to gene mapping and genetic maps might appear somewhat outdated, not to say useless. However, we thought that it might be interesting to reconsider this subject for at least three reasons. The first is that gene mapping has been a major component of the activities of mouse geneticists during most of the twentieth century; it is then interesting, if only from a historical point of view, to briefly describe the techniques and methods that have made the genetic map of the mouse the richest and most documented map of all mammals, including humans, for nearly 50 years. The second reason is more fundamental and refers to the many mutations that occur spontaneously in the breeding nuclei of inbred strains or those that are induced by mutagenic agents. All these mutations are initially characterized by an abnormal phenotype and some of them may appear of potential interest, for example, as models of human diseases. However, annotating and characterizing all these mutations requires that they be first carefully located on a chromosome and analyzed at the molecular level, when relevant.

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Notes

  1. 1.

    The structure of the mitochondrial genome (or mtDNA) is discussed in Chap. 5; here we consider only the genes in the nuclear genome.

  2. 2.

    In this type of cross, the classical recessive allele Tyr c (albino) cannot be used because it has an epistatic interaction with pink-eyed dilution, affecting eye and coat color, which makes phenotyping difficult.

  3. 3.

    +/d? indicates that the actual genotype of the mouse is not known. It may be either +/+ or +/d.

  4. 4.

    Reading the original publications is sometimes difficult due to the use of a nomenclature system different from the one in use nowadays. The dilute locus, for example, was designated “density” with two alleles: D and d. Nowadays, the same gene is symbolized Myo5a d.

  5. 5.

    A review by Dr. Eva Eicher from The Jackson Laboratory is a rich source of information concerning the historical aspects of mouse gene mapping and the progressive development of the genetic map in this species (Eicher 1981).

  6. 6.

    It is now established that there are very few genes on the Y chromosome.

  7. 7.

    The presumption that the twenty LGs identified at that time were each located on different chromosomes was shown to be wrong. In fact, a few genes were still mis-assigned and one LG was not yet identified.

  8. 8.

    If the alleles at the A and B locus were not linked or if the linkage was not known, the symbols for the genotypes would be: A/A; b/b for the male and a/a; B/B for the female.

  9. 9.

    When one of the mutant alleles (M) is dominant over wild type (+): the phase is +M/am for coupling and aM/+m for repulsion. In other words, the dominant alleles are associated on the same chromosome when in coupling.

  10. 10.

    Many of these software programs are listed at: http://www.jurgott.org/linkage/ListSoftware.html. The most popular are MAPMAKER, MAPMANAGER and GENE LINK.

  11. 11.

    When the computed genetic distances are short or very short (<3 cM), it is recommended to express them with the lower and upper limits of the exact 95 % confidence interval calculated from the binomial distribution, as they appear in Table D5 and D6 (pp. 303–304) of Silver’s book Mouse Genetics: concepts and application, Oxford University, 1995. This textbook is freely available at the Mouse Genome Informatics website.

  12. 12.

    The physical (or DNA) size of the genome is estimated to be 2.7 Gb, and the mouse genetic (meiotic) map is estimated to span ~1,600 cM.

  13. 13.

    This equivalence between cM and kb/Mb applies to the mouse only. In the human species, 1 cM is equivalent to ~0.7–1 Mb of DNA.

  14. 14.

    http://www.informatics.jax.org/silverbook/frames/frame9-1.shtml.

  15. 15.

    Preparing a four-point backcross involving traditional or classical genetic markers, i.e., those that are scored by scrutinizing the mice one after the other, requires a lot of crosses because the markers in question are almost always in independent stocks or strains and first have to be gathered in the same stock by sexual reproduction.

  16. 16.

    Most of the genes used for mapping in the past are now cloned and their DNA sequence is known. For LG I, for example, Tyr is the gene encoding tyrosinase and Oca2 (oculocutaneous albinism II) is a gene encoding a transmembrane transporter essential for normal pigmentation. Both genes are involved in the production of melanin, and both are cloned and sequenced. The two genes can then be considered under two aspects: either as a mouse with a specific coat color, or as fluorescent dots on a mouse chromosome (see Chap. 3). In this particular case, it is chromosome 7 (bearing the whole of LG I).

  17. 17.

    The breakpoint of the reciprocal translocation T(2;8)26H on chromosome 2 is within the Agouti locus and inactivates this gene. Mice homozygous for the translocation, which are easy to identify by analysis of the karyotype, are also non-agouti (with a black coat color). This observation (and others) allowed it to be established that LG V (including the Agouti locus) was on Chr 2.

  18. 18.

    Accumulation of these new mutant alleles was, in part, a direct consequence of the use of the mouse as a model organism for the evaluation of the effects of radiation or of chemical mutagens on the genome, and an indirect consequence of inbreeding as a mating system. Inbreeding has no effect on the mutation rate, but it increases the chance that individuals will be homozygous for recessive mutations, which, accordingly, are more easily identifiable.

  19. 19.

    During the years 1965–1975, when the genetic map of the mouse was expanding, researchers at Harwell MRC and The Jackson Laboratory were using the so-called linkage testing (or linkage tester) stocks. These stocks were homozygous for up to seven carefully selected recessive, fully viable, and fully penetrant coat color markers mapping to different chromosomes. The phenotype of each of these markers could be detected independently, with no interference from the other markers. One of these stocks was the famous PT stock, which was extensively used at Oak Ridge by W.L. & L.B. Russell for estimating the rate of induced mutations either with chemicals or radiation. The PT stock was homozygous for seven markers on five chromosomes: a/a; b/b; c ch-p/c ch-p; d-se/d-se; wa1/wa1.

  20. 20.

    Repeated units such as T, CA, CT, and CAG are among the most common.

  21. 21.

    In fact, the microsatellites are more mutable than most other molecular markers previously described, but their mutation, in general, generates a novel allele that is not identical to any of the parental alleles. In these conditions the structural instability does not result in a confusion. It may, however, be a problem when microsatellites are used for the genetic monitoring of inbred strains (see Chap. 9).

  22. 22.

    Around 70 % of SSLPs (microsatellites) or SNPs have been found to be polymorphic between any two strains derived from progenitors of independent (wild) origins of the same Mus genus. Altogether, this means that around 30,000 SNPs or SSLPs could (potentially) be used for the purpose of mapping in a cross involving two inbred strains derived from two different subspecies.

  23. 23.

    A bin is a group of syntenic genetic markers that have not been separated (ordered) by meiotic recombination in a given cross.

  24. 24.

    The mapping of these microsatellites has been achieved in two successive steps. First, all the 982 DNA samples of the backcross progeny were initially typed for 78 primary anchor loci spanning the entire genome, with 3–6 anchors per chromosome. In a second step, only the DNA samples demonstrated to be recombinant in one or the other of these intervals tagged by the 78 primary anchor loci were typed for the greatest possible number of markers located (or presumed to be located) in these regions.

  25. 25.

    In fact, and as we shall see in Chap. 5, the mouse genome has been sequenced by using a global strategy known as whole-genome sequencing or WGS. However, the physical map of the mouse genome, established by anchoring a variety of DNA clones on the genetic map, has been helpful in many experiments of positional cloning, and is still used for the analysis of quantitative traits.

  26. 26.

    This is sometimes referred to as a “magnifying glass effect.”.

  27. 27.

    Reverse genetics is the opposite approach: its aim is to characterize the function of a gene by analyzing the consequences at the phenotypic level of alterations occurring spontaneously or engineered by researchers at the DNA level.

  28. 28.

    5–6 markers for the largest chromosomes, 4–5 for the medium-sized and 3 for the smallest is ideal.

  29. 29.

    The first sample of 50–60 mutant mice generally consists of the first offspring of the larger population.

  30. 30.

    This is why it is best to perform genotyping as early as possible, before weaning.

  31. 31.

    As we will explain in the next chapter, gene density is extremely variable from one genomic region to the next. Accordingly, these estimations must be considered only as indications.

  32. 32.

    Because there is contiguity in their sequence.

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Guenet, JL., Benavides, F., Panthier, JJ., Montagutelli, X. (2015). Gene Mapping. In: Genetics of the Mouse. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-44287-6_4

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