Genetics of Complex traits II

  1. Two main approaches exist to mapping QTLs (define), the genes that contribute to complex traits
    Quantitative Trait Loci (QTLs): genes that control the expression of continuous traits

    Direct QTL mapping and association mapping (pg 703-704)
  2. The basic idea underlying both approaches is the same, and it relies on ______ _______ to produce individuals with different genetic compositions. In direct QTL mapping, _______ occurs during several generations of a series of crosses controlled by the researcher; in _______ mapping the _________ already happened during the history of a randomly breeding population. In both cases, investigators ultimately test for statistical correlations between ______ in different regions of the genome and the particular phenotypic character of interest. These correlations can often pinpoint genetic changes responsible for _______ in the phenotype
    • genetic recombination
    • recombination 
    • association
    • recombination
    • markers
    • variations
  3. Direct QTL mapping
    identifying QTLs by controlled crosses
  4. If researchers can find ______ that correlate with QTLs for a commercially valuable trait, then they can develop useful strains that _______ the expression of that trait by finding recombinants that contain particular combinations of alleles of several QTLs. In such applications, the researchers do not necessarily have to identify the particular genes that contribute to the _______; instead, they just need to find _________ linked closely enough to the QTLs so taht DNA analysis will identify the strains most likely to have the most _______ _______.
    • markers 
    • maximize 
    • phenotype
    • polymorphisms
    • desirable phenotypes
  5. More than two thousand years of domesticated breeding has resulted in the tomatoes used in today's cuisines. Some domesticated tomatoes have fruits that are hundreds of time _____ than thsoe of their wild ancestors, which were originally from Mexico. The size _______ leading to today's large domesticated tomato occurred through the accumulation of ______ in many different genes over _______ of generations of selection
    • larger
    • increase
    • mutations
    • thousands
  6. To identify the relevant genes, researchers started with two closely related species, easily interbred, that exhibited phenotypes at the extreme ends of the size range: Solanum lycopersicum (large) and Solanum pennellii (small). What was the process? (7-story)
    define isogenic lines
    isogenic lines: globally homozygous strains in which all individuals have the identical (homozygous) alleles at all of the genes

    pg 704-705
  7. Why can we represent them as being p/p or l/l for every gene or marker locus at which the two strains were different
    because the starting strains of S. pennellii and S. lycopersicum were isogenic
  8. The F1 are thus genetically ______ and _______ (p/l) at every one of these loci, while each BC1 tomato is either ________ or ________. What is the advantage of beginning with isogenic strains?
    • identical and heteozygous (p/l)
    • homozgyous l/l or heterozygous p/l
    • The BC1 progeny will inherit different single known alleles of molecular markers specific to S. pennellii or S. lycopersicum that can be tracked easily
  9. The researchers then calculated the avg ______ of the tomatoes _______ and _______ for each marker. In the cases of most of these marker loci, the mean weights of the homozygotes and the heterozygotes were the ______. But for markers linked to the relevant QTLs, the mean weights were ________.
    • weight
    • homozygous and heterozygous
    • same 
    • different
    • *(To determine if a calculated difference was significant, the scientists used a version of the Lod score mapping statistic described in Chapter 10 on p. 351). Using this method, the investigators discovered 28 QTLs that influence tomato size
  10. As an example of the direct QTL mapping technique, suppose the starting strain of S. pennellii was homozygous for allele A1 of a particular marker, the isogenic S. lycopersicum strain was homozygous for allele A2, and the heterozygous p/l (A1/A2) BC1 tomatoes are significantly ______ than the l/l homozygous (A2/A2) BC1 tomatoes. The marker is thus linked to a _____ for tomato size. Plant breeders can then predict that tomatoes with the A1 allele will likely be ______ than those with the A2 alleles of this marker. Such predictions do not require this marker to be the ________ responsible for the trait, only that the marker differences be linked to the responsible _________
    • smaller
    • QTL
    • larger
    • polymorphism
    • polymorphism
  11. Rough mapping does not identify the causal gene for the ____, but instead establishes a chromosomal segment in which the ______ could lie, and whose boundaries are defined by the ______ ______ molecular markers. In most such studies, this region is between 1 and 10cM long, and could include over _____ genes. Although successful breeding programs may not require scientists to find the _____ gene, good reasons often exists for extending the research to accomplish this goal
    • QTL
    • gene
    • nearest linked
    • 100 genes
    • causal
  12. In the study just described, the QTL with the largest effect on size was called fw2.2 (fruit weight 2.2); the S. lycopersicum alleles of fw2.2 may _______ fruit weight by up to ___%. In order to begin to understand what molecular factors govern tomato size, investigators wanted to identify the fw2.2 causal gene through a process called ____ ____
    • increase
    • 30%
    • fine-mapping
  13. Explain fine mapping (5-story)
    define introgression
    • Introgression: the small line of the other species (S. pennelli) in a region of QTL belonging to a congenic individual that is almost purely isogenic (S. lycopersicum)  (except that region of its QTL)
    • pg 705-706
  14. Final step of Fine mapping in detail: Researchers cloned the suspect fw2.2 gene from the pennellii genome and introduced it as a _______ into lycopersicum. The result, was that the ______ made the lycopersicum tomatoes substantially ______. This phenotypic rescue test was possible because the pennellii fw2.2 allele is ______, while the recessive lycopersicum allele causes a reduced function. In other words, the lycopersicum allele is _________
    • transgene
    • transgene
    • smaller
    • dominant
    • hypomorphic
  15. The standard QTL mapping methods just described require controlled matings of phenotypically different individuals; but for many organisms including humans, such experiments are neither ______ nor _____. In addition, the number of recombination events that occur in the experimental crosses performed limits the resolution of standard ______ _______
    • practical nor ethical
    • QTL mapping
  16. Fortunately, nature already provides an alternative way to map QTLs: Geneticists can use a method called association mapping to take advantage of past _________ events that occurred in the ________ of present-day individuals. As the fig shows, association mapping is really just an extension of _______ mapping (depicts order and distances between loci), in which _______ occurs not over just a single generation, but instead ______ over many generations
    Image Upload 1
    • recombination 
    • ancestors 
    • linkage
    • recombination 
    • accumulates
  17. What is the idea behind association mapping?
    pg 706 right bottom
  18. In association mapping, scientists test present-day individuals for genetic variants that are statistically _______ with differences in ______. For example, if the phenotype is a condition such as coronary artery disease, then the goal is to find a marker whose frequency in a population of patients is significantly _______ than that in a population of _______ controls. If the researchers find variants strongly _______ with the condition, these markers must be closely linked to QTLs influencing whether people will develop coronary artery disease
    • correlated
    • phenotype
    • greater
    • nondiseased
    • correlated 
    • linked
  19. To understand how geneticists perform association mapping, we need first to examine how variants at different sites across the genome tend to be ______ with respect to each other in ______ populations. The basic question is whether alternative variants at one site are ______ _______ with variants at other sites, or instead whether they are ______ _______
    • organized
    • natural 
    • randomly associated 
    • statistically correlated
  20. For example, in a hypothetical population, nucleotide position 300500 on chromosome 1 has two variants (A and T) in _____ frequency, while nucleotide position 300600 on the same chromosome has two varaints (G and C), also in ______ frequency. With free ________ between sites, we would expect to have four different _____ _____ ____ types (______) among gametes produced by parents in this population: A-G, A-C, T-G, and T-C in frequencies of ___% each
    • equal
    • equal
    • recombination
    • two-site haploid type (haplotypes)
    • 25%
  21. In such a case, the presence of an A at site 1 ______ provide any information about the variant at site 2, which is _____ likely to be a G or a C. In such a case, no _______ exist between the identities of the alleles at the two sites, and we would then say that variation at these two sites is in ______ ______
    • doesn't 
    • equally
    • correlations
    • linkage quilibrium
  22. An extreme departure from random association would be where only _____ ______ are present, for example A-G and T-C, each in a frequency of ____. In the latter case, a perfect positive correlation exists between variants at the two sites:
    • two haplotypes
    • 0.5
    • positive
    • When we find an A at site 1 then we can predict with certainty that we will see a G at the second site
  23. Variants T and C are also ______ ______ correlated with each other. When the variants of two loci are correlated, then we say the variation is in _____ ______
    • perfectly positively
    • linkage disequilibrium (LD)
  24. LD is measured by a statistic, D, which can be adjusted so that it ranges from 0 (for no _______ as in the case of linkage equilibrium) to 1 (indicating a _____ _______ between variation at two sites)
    • correlation 
    • perfect correlation
  25. As we compare sites further and further apart along a ________, with greater genetic map distances between them, LD gradually ______ to 0 because more possibilities exist for ______ ______ to disrupt allele associations
    • chromosome
    • decays
    • genetic recombination
  26. Geneticists often illustrate this concept by a plot of _____ LD values which has the SNPs listed across the top of a ______ diagram of diamonds and the shade of color (from purple to green) of each diamond indicates the strength of LD between the SNPs compared. The fig shows through an analogy how such plots are made and interpreted; in the figure, the colors indicate the _____ between six cities along the west coast of the the US rather than LD values
    Image Upload 2
    • pairwise
    • traingular
    • distances
  27. Rates of ________ in humans avg roughly 1 * 10-8 crossover events per generation between _____ base pairs. However, ________ tends to be clustered into _______ of genetic exchange. This discontinuity of recombination, as well as the ______ of when and where recombination occurs over evolutionary time, leads to _______ in LD across chromosomes for human populations. These _______ can be tracked by the presence of ____ ______ on triangular diagrams
    Image Upload 3
    • recombination 
    • adjacent 
    • recombination
    • hotspots
    • randomness 
    • discontinuities 
    • discontinuities
    • LD blocks
  28. The presence of LD in genomes makes it possible for scientists to assay variation at _____ polymorphisms at different ______ across chromosomes and then test for statistical correlations between the _____ and ______ of interst
    • random 
    • locations
    • variants and phenotype
  29. When carried out on a genome-wide scale, such a survey is called a _____ _____ ______ study. Ideally you would want to assay every _____ ______ in the genome to discover the most likely causal variant(s)  for the difference in _______. However, genotyping to this resolution would require _____-_____ sequencing, and the cost of high-quality full genome sequencing is still too high for studies involving the tens of thousands of indviduals needed
    • Genome-Wide Association Study (GWAS)
    • DNA variant
    • phenotype
    • whole-genome
    • *Thus, researchers performing the GWAS studies to date have used DNA microarrays that assay millions of common SNPs tagging different regions of the genome
  30. To carry out a GWAS analysis, scientists assess the frequencies of ______ distributed across _____ in large samples of cases and controls, and then use the ____ ______ test to locate variants whsoe frequencies are ______ correlated with the ______ of interest. (Explain)
    • variants
    • genomes 
    • chi-square
    • positively 
    • phenotype
    • In other words, to identify a QTL, the chi-square test for a tightly linked variant would need to show a significant difference between the frequencies for that variant in the patient and control populations; the null hypothesis is that no difference exists
  31. Performing tests on millions of SNPs leads to a problem of _____ ______, (why?)
    • false positives
    • because with this many loci, a large number of SNPs may appear to differ in their frequencies between affected cases and control even if these differences reflect only chance sampling errors
Card Set
Genetics of Complex traits II
Ch 21.2