7the controlling regions appeared to be far from the genes they affect. Now ENCODE
researchers have discovered that small segments of junk DNA are often quite close
to genes they control.
The result of the ENCODE studies is an annotated road map of much of this
DNA. The system of switches select the genes used in a cell as well as determine
when they are used and their fate, e.g. whether a cell becomes a liver cell or a neu-
ron. Many complex diseases appear to be caused by tiny changes in hundreds of
gene switches. These fi ndings will have immediate applications for understanding
how alterations in the non-gene parts of DNA contribute to human diseases, which
may in turn lead to new treatments. They can also help explain how the environment
can affect disease risk. In the case of identical twins, small changes in environmen-
tal exposure can slightly alter gene switches, with the result that one twin gets a
disease and the other does not.
Gene switches are linked to a range of human diseases: multiple sclerosis, lupus,
rheumatoid arthritis, Crohn’s disease, celiac disease and even to traits like height.
The discoveries also reveal the genetic changes that are important in cancer and
why. Most of the thousands of DNA changes in cancer cells were found not in
genes, but in the so called “junk DNA”. The challenge is to fi gure out which of those
changes are driving the cancer’s growth, which has implications for the manage-
ment of cancer. In prostate cancer, e.g. there are mutations in important genes that
do not readily respond to drugs. ENCODE, by showing which regions of the “junk
DNA” control those genes, provides another approach to attack them by targeting
the controlling switches.
Chromosomes
Each human chromosome is a long linear double-stranded DNA molecule (except
the mitochondrial chromosome) ranging in size from 50 to 250 million base pairs.
An average chromosome contains 2,000–5,000 genes within 130 million base
pairs and is equal to about 130 cM of genetic material. A typical microband on a
chromosome contains 3–5 million bp and 60–120 genes. There are approximately
400 million nucleotides in a human chromosome, but only about 10 % of them
actually code for genes; the rest may play different roles such as regulating gene
expression.
The complex of DNA and proteins of a chromosome is called chromatin and
consists of histones and non-histone proteins. The basic structural unit of chromatin
is a nucleosome – a complex of DNA with a core of histones. The amount of DNA
associated with each nucleosome is about 200 base pairs. Nucleosomes are further
compacted to solenoids which are packed into loops and each of these contains
about 100,000 base pairs of DNA. The loops are the fundamental units of DNA
replication and/or gene transcription. A karyotype describes an individual’s chro-
mosome constitution. Each of the 46 human chromosomes can now be counted and
characterized by banding techniques.
Molecular Biological Basis of Personalized Medicine