Page 94 - Genetics_From_Genes_to_Genomes_6th_FULL_Part3

388 Chapter 11 Analyzing Genomic Variation

the genetic disease, but possession of this sequence infor- Figure 11.25 SNP patterns consistent with inherited traits.
mation does not guarantee that geneticists will be able to Each oval represents a copy of a gene, so each person corresponds
identify the responsible mutation(s). One problem is tech- to two ovals. Common variants are in different shades of gray; while
nical: No genome sequence is 100% accurate or 100% com- orange, blue, yellow, or green symbolize different rare variants in the
same gene. (a) Variants that could cause a dominant trait. Within a
plete. All sequencing methods have a low but real error rate family, affected individuals will be heterozygotes for the same rare
in identifying nucleotides, and random sampling of DNA variant. Unrelated affected people may be heterozygotes for different
fragments will leave some regions of the genome un- rare variants in the same gene. (b) Variants that could cause a
sequenced. These issues can be minimized by coverage of recessive trait. In consanguineous families, affected individuals will be
10 or more genome equivalents, but they cannot be elimi- homozygotes for a single variant they inherit by descent from a recent
common ancestor. The affected children of unrelated people most
nated completely. likely are compound heterozygotes who inherit different rare mutations
An even more fundamental problem is that the amount in the same gene, one from each parent. In both (a) and (b), unaffected
of variation among human genomes is huge. We saw at the controls may or may not be related.
beginning of this chapter that any person’s genome differs (a) SNPs that could cause a rare dominant trait
at more than 3 million locations from the standard RefSeq A ected A ected
human genome. How can we tell which of these millions of
DNA polymorphisms causes a patient’s disease? Our abil- Within a family
ity to deal with whole-genome sequences is still so limited Heterozygous for same rare variant
that in many cases, the responsible mutation has yet to be
identified. It should be lurking in the sequence, but it frus- A ected A ected
tratingly remains hidden in front of our noses. Unrelated
Despite these issues, investigators have been able to individuals
marshal the results of several types of data analysis, some-
times supported by inspired guesswork, to find an increas- Likely heterozygous for di erent
rare variants in the same gene
ing number of disease genes. We focus in this section on
the types of clues geneticists use to identify disease-causing Una ected Una ected
mutations within whole-genome/exome sequences. However,
it is crucial to keep in mind that these methods are not, at Controls
least not yet, always successful. Heterozygous or homozygous
for common alleles
Clues from disease transmission patterns
(b) SNPs that could cause a rare recessive trait
The underlying logic of whole-genome or whole-exome
sequencing requires that the DNA variants that are disease A ected A ected
alleles will be rare in the population. This basic assumption Within a family
allows scientists to make predictions about which of the (consanguineous)
variations in a patient’s genome could be responsible for
the disease. These predictions depend on what pedigrees Homozygous for the same rare variant
say about the disease’s inheritance: Is the disease allele re-
cessive or dominant? Is it sex-linked or autosomal? Is the Within a family A ected A ected
penetrance complete or incomplete? Each of these inheri- (non-
tance modes is consistent only with particular molecular consanguineous)
genotypes at a candidate locus. Same two rare variants in the same
In the case of a rare dominant condition, it is highly gene in all a ected family members
likely that the patient would be heterozygous for the caus-
ative allele. Related patients should have the same rare A ected A ected
mutant allele, whereas unrelated patients might have dif- Unrelated
ferent mutations in the same gene (Fig. 11.25a). If the individuals
condition is recessive, geneticists would first focus their Di erent rare variants
attention on rare mutations that are homozygous in the in the same gene
patient’s genome, particularly if the parents are related Una ected Una ected
even distantly. If the condition is recessive and the parents
are unrelated, the patient could instead be a compound Controls
heterozygote, with two different mutant alleles of the same
gene (Fig. 11.25b). To check this latter scenario, geneti- Heterozygous or homozygous (not shown)
for common alleles; heterozygous
cists would look in the patient’s DNA for a gene affected for rare variant