Since the 1960s, scientists have been ﬁnding second and
third layers of information important in directing development
elsewhere—in the noncoding DNA and even totally outside the
DNA sequences. So what are these other regulatory systems?
Te second layer appears to be the product of the abundant
“RNA-only genes,” formerly believed to be “junk,” that are found
in the vast oceans of non-protein-coding DNA. Tey form
a parallel regulatory system that generates single-stranded
microRNAs (miRNAs) and short interfering RNAs (siRNAs) (see
p. 105). Tese small RNA molecules are “control freaks” that can
act directly on DNA, other RNAs, or proteins. Tey also can tame
or inactivate aggressive (jumping) genes, called
tend to replicate themselves and then insert the copies into distant
DNA sites, disabling or hyperactivating those genes.
Small RNAs control timing of programmed cell death during
development and can also prevent translation of another gene. Mu-
tations in these RNA-only areas have already been linked to several
conditions including prostate and lung cancers and schizophrenia.
It takes relatively few genes to build a human being. Our
complexity is the result of the small RNAs that control the ex-
pression of genes especially during growth and diﬀerentiation.
Nucleotide sequences of these RNA-specifying DNA areas are
now worked out and biochemical companies are investing heav-
ily in gene therapy research. Tey are especially hot on synthe-
sizing RNA-interfering drugs to silence or shut down particular
genes to treat age-related macular degeneration, Parkinson’s
disease, cancer, and a host of other disorders.
Epigenetic marks form the third layer of gene controls. Tis
continually changing information is stored in the proteins and
chemical groups that bind to the DNA and in the way chro-
matin is packaged in the cell. Within cells, chemical tags such
as methyl and acetyl groups bound to DNA segments and to
histones determine whether the DNA is available for transcrip-
tion (acetylation) or silenced (methylation). Epigenetic marks
also account for the inactivation (by methylation) of one of the
female’s X chromosomes in the early embryo.
Epigenetic marks or lack of them may predispose a cell for
transformation from normal to cancerous, and even slight de-
viations in the epigenetic marks on speciﬁc chromosomes can
result in devastating human illness.
Epigenetic marks also underlie the phenomenon called ge-
nomic imprinting. For most genes, the maternal and paternal
genes turn on or oﬀ at the same time. Tis balance is upset dur-
ing gametogenesis when certain genes in both sperm and eggs
are modiﬁed by the addition of a methyl (—CH
) group, a pro-
. Genomic imprinting some-
how tags the genes as paternal or maternal and confers
important functional diﬀerences in the embryo. Te developing
embryo “reads” these tags, and then either expresses the moth-
er’s gene while the father’s version remains idle or vice versa. In
each generation, the old imprints are “erased” when new gam-
etes are produced and all the chromosomes are newly imprinted
according to the sex of the parents.
in Gene Expression
Provide examples illustrating how gene expression may be
modiﬁed by environmental factors.
In many situations environmental factors override or at least inﬂu-
ence gene expression. Our genotype (discounting mutations) is as
unchanging as the Rock of Gibraltar, but our phenotype is more
like clay. If this were not the case, we would never get a tan, women
bodybuilders would never be able to develop bulging muscles, and
there would be no hope for treating genetic disorders.
Sometimes, such maternal factors as drugs or pathogens alter
normal gene expression during embryonic development. ±ake,
for example, the case of the “thalidomide babies” (discussed on
p. 1083). As a result of their mothers taking that sedative, the em-
bryos developed phenotypes (ﬂipperlike appendages) not directed
by their genes. Such environmentally produced phenotypes that
mimic conditions that may be caused by genetic mutations (per-
manent transmissible changes in the DNA) are called
Equally signiﬁcant are environmental factors that may inﬂu-
ence genetic expression a²er birth, such as the eﬀect of poor
infant nutrition on brain growth, general body development,
and height. In this way, a person with “tall genes” can be stunted
by insuﬃcient nutrition. Furthermore, part of a gene’s environ-
ment consists of the inﬂuence of other genes. For example, hor-
monal deﬁcits during childhood can lead to abnormal skeletal
growth and proportions, as in cretinism, a type of dwarﬁsm
resulting from hypothyroidism.
Check Your Understanding
Which of the following factors may alter gene expression?
Other genes, measles in a pregnant woman, lack of key
nutrients in the diet.
For answers, see Appendix H.
Mendel’s writings underlie mainstream thinking about heredity,
but some genetic outcomes do not ﬁt his rules. Among these non-
traditional types of inheritance are inﬂuences due to RNA-only
genes, to chemical groups attached to DNA or histone proteins,
conferred by mitochondrial DNA.
Regulation of Gene Expression
Describe how RNA-only genes and epigenetic marks affect
Our genome is a biochemical system of awesome complexity,
with three basic levels of controls. Te protein-coding genes
that we have been describing to this point only make up the ﬁrst
level and account for less than 2% of the DNA of a human cell.
Tis is the part of the genome traditionally considered to be a
“blueprint” for protein structure.