13Although CNVs confer a risk of disease, they may not be suffi cient by themselves
to lead to a specifi c disease outcome, leading to speculation that additional risk fac-
tors may account for the variation. The factors underlying the phenotypic variation
associated with seemingly identical genomic alterations have not been entirely clear
and present challenges for clinical diagnosis, counseling, and management. A “two-
hit,” or second-site model is based on the observation that affected persons with a
microdeletion on chromosome 16p12.1 are more likely to have additional large
CNVs than are controls (Girirajan et al. 2010 ). These data supported an oligogenic
basis, in which the compound effect of a relatively small number of rare variants of
large effect contributes to the heterogeneity of genomic disorders, and provided
testable predictions of the cause of syndromic disorders and those with phenotypic
variation. In a further study, these authors observed considerable variation in the
phenotypes associated with several recurrent specifi c CNVs that are relatively prev-
alent (Girirajan et al. 2012 ). This fi nding was complicated by the identifi cation of
apparently normal or mildly affected carrier parents with 16p11.2,15,17,18
1q21.1,32 or 16p12.121 CNVs, suggesting that these variants are critical but not
sole determinants of phenotype. These data are consistent with locus heterogeneity
and a modest number of high-impact variants contributing to a spectrum of disease
severity within families. The interpretation of variants associated with phenotypic
variation remains challenging at the clinical level, but this study provides help in
understanding factors that contribute to the phenotypic outcome, which may be
used for counseling. It explains why persons with the same chromosomal abnormal-
ity may have very different clinical outcomes: some of them may simply have a
second genetic event that makes matters worse for them. The fi ndings of the study
represent a step toward deconvoluting the effect of CNVs in disease and understand-
ing, more broadly, the causes of neurologic disease. The analysis shows that the
phenotypic variation of some genomic disorders may be partially explained by the
presence of additional large variants.
Insertions and Deletions in the Human Genome
Emory University scientists have identifi ed and created a map of 415,436 insertions
and deletions (INDELs) in the human genome that signal a little-explored type of
genetic difference among individuals (Mills et al. 2006 ). INDELS are an alternative
form of natural genetic variation that differs from the much-studied SNPs. Both
types of variation are likely to have a major impact on humans, including their
health and susceptibility to disease.
SNPs are differences in single chemical bases in the genome sequence, whereas
INDELs result from the insertion and deletion of small pieces of DNA of varying
sizes and types. If the human genome is viewed as a genetic instruction book, then
SNPs are analogous to single letter changes in the book, whereas INDELs are
equivalent to inserting and deleting words or paragraphs. INDELs were discovered
using a computational approach to re-examine DNA sequences that were originally
generated for SNP discovery projects. INDELs are distributed throughout the
Molecular Biological Basis of Personalized Medicine