Noncoding regulatory RNAs. Of the 80% of the genome dedicated to regulatory functions, the vast majority is transcribed into RNAs—micro-RNAs and long noncoding RNAs (described later)—that are never translated into protein, but can regulate gene expression
Mobile genetic elements (e.g., transposons). Remarkably, more than one-third of the human genome is composed of such “jumping genes.” These segments can cruise around the genome, and are implicated in gene regulation and chromatin organization.
Special structural regions of DNA, including telomeres (chromosome ends) and centromeres (chromosome “tethers”)
Importantly, many genetic variations (polymorphisms) associated with diseases are located in non–proteincoding regions of the genome. Thus, variation in gene regulation may prove to be more important in disease causation than structural changes in specific proteins. Another surprise that emerged from genome sequencing is that any two humans are typically >99.5% DNA-identical (and are 99% sequence-identical with chimpanzees)! Thus, individual variation, including differential susceptibility to diseases and environmental exposures, is encoded in <0.5% of our DNA (importantly, this still represents about 15 million base pairs).
The two most common forms of DNA variation in the human genome are single-nucleotide polymorphisms (SNPs) and copy number variations (CNVs).
SNPs are variants at single nucleotide positions and are almost always biallelic (only two choices exist at a given site within the population, such as A or T). More than 6 million human SNPs have been identified, with many showing wide variation in frequency in different populations. The following features are worthy  of note:
SNPs occur across the genome—within exons, introns, intergenic regions, and coding regions.
Roughly 1% of SNPs occur in coding regions, which is about what would be expected by chance, because coding regions comprise about 1.5% of the genome.
SNPs located in noncoding regions can occur in regulatory elements in the genome, thereby altering gene expression; in such instances the SNP may have a direct influence on disease susceptibility.
SNPs can also be “neutral” variants with no effect on gene function or carrier phenotype.
Even “neutral” SNPs may be useful markers if they happen to be coinherited with a disease-associated gene as a result of physical proximity. In other words, the SNP and the causative genetic factor are in linkage disequilibrium.
The effect of most SNPs on disease susceptibility is weak, and it remains to be seen if the identification of such variants, alone or in combination, can be used to develop effective strategies for disease prediction or prevention.
CNVs are a form of genetic variation consisting of different numbers of large contiguous stretches of DNA; these can range from 1000 base pairs to millions of base pairs. In some instances these loci are, like SNPs, biallelic and simply duplicated or deleted in a subset of the population. In other instances there are complex rearrangements of genomic material, with multiple alleles in the human population. CNVs are responsible for several million base pairs of sequence difference between any two individuals. Approximately 50% of CNVs involve gene-coding sequences; thus, CNVs may underlie a large portion of human phenotypic diversity.
It is important to note that alterations in DNA sequence cannot by themselves explain the diversity of phenotypes  in human populations; moreover, classical genetic inheritance cannot explain differing phenotypes in monozygotic twins. The answers to these conundrums probably lie in epigenetics—heritable changes in gene expression that are not caused by alterations in DNA sequence (see later).
Even though virtually all cells in the body have the same genetic composition, differentiated cells have distinct structures and functions arising through lineage-specific programs of gene expression. Such cell type–specific differences in DNA transcription and translation are regulated by epigenetic modifications that consist of several changes that profoundly influence gene expression, including:
Fig. 1.2 ). Genomic DNA is packed into nucleosomes, which are composed of 147