Chapter 5 – Genetic Contributions to the Development of Obesity
Questions
1. List three reasons to study the genetic basis of population variations in adiposity and
obesity.
2. List three reasons why the identification of genes may not be needed as prognostic
indicators for prevention of obesity.
3. Define the terms, allele, chromosome, homozygous, heterozygous, genomes, genes,
genotype and recessive, needed to understand deeper analyses of the genetics of
obesity.
4. Explain the current estimate of heritability of the genetics of obesity, and its
importance in studying the genetics of obesity.
5. Identify three novel approaches used in human models to study the genetics of
obesity.
6. Identify the main conclusions of animal and human research and the genetics of
obesity.
7. Explain the importance of considering fetal programming and epigenetics in the
development of obesity.
Understanding Obesity: Biological, Psychological and Cultural Influences. Edited by Sharon Akabas, Sally Ann Lederman
and Barbara J. Moore. © 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.
Chapter 5 – Genetic Contributions to the Development of Obesity
Answers
1. Some investigators want to understand the evolutionary basis of our current
population distribution of adiposity (8-12) and the “genetic architecture” of the
trait at present. A second reason to study the genetics of obesity is to identify
genes that can be used as prognostic factors to indicate who is likely to become
obese so that they can be given preventive therapy. There are, however, at least
three reasons to question the validity of this goal. A third reason people study
the genetics of obesity is to identify genes that moderate the safety and/or
efficacy of treatments.
2. First, one could probably do such prognostication just as well, if not better, by
using parental adiposity levels as the predictive factors. This approach would not
require the expensive and difficult process of identifying specific genes. Second,
given current population levels of obesity, we can simply predict that everyone
will be obese and we would be correct at least one-third of the time. Third, even
if we had such a prognostic factor, at present we do not have a prevention
strategy that is known to work.
3. Genes are the units of heredity. Genes are ordered sequences of DNA
(deoxyribonucleic acid) that store information. A chromosome is a single, long
molecule of DNA that contains many genes. The information stored in DNA may
be expressed through either RNA (ribonucleic acid) or proteins. Variations in
DNA sequence are caused by mutation. An allele is one specific sequence of the
DNA in a gene. Alleles can differ greatly with respect to RNA and protein
expression. For most genes in humans, there are two alleles, one on the
chromosome inherited from the mother and the other on the chromosome
inherited from the father. If the alleles of a given gene are the same, then the
person is homozygous for that gene. If the alleles are different, then the person
is heterozygous for that gene. The particular pair of alleles that a person carries
for a given gene is called his or her genotype. Recessive alleles are those that are
expressed only when an individual is homozygous for the gene. If there is only
one copy of a recessive allele, it is overpowered by the allele on the other
chromosome, the dominant allele. An observable characteristic such as body
weight is called a phenotype. A phenotype may reflect both genetic and
environmental influences. The genome is the complete set of genetic
information for an individual.
4. Current heritability estimates are in the range of 60% to 70% seem to be the
most accurate for BMI. Some people who wish to make beneficial changes to
human health by altering the environment seem to see these figures as
Understanding Obesity: Biological, Psychological and Cultural Influences. Edited by Sharon Akabas, Sally Ann Lederman
and Barbara J. Moore. © 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.
threatening or disheartening. However, heritability estimates of 60% to 70%
imply that environmental factors explain the remaining 30% to 40% of the
variance in BMI, which is a substantial proportion of the total variance. It implies,
for example, that moving people merely one standard deviation down in
environmental risk (i.e., making a moderate change to the environment) could
decrease average BMI by two units. This would correspond to roughly a 10%
reduction in relative weight, roughly the amount that can be achieved with the
best available pharmaceuticals today, illustrating the power of the environment
even in the face of strong heritability.
5. Transcriptomics, also called genome-wide expression profiling, examines the
expression levels of mRNA in order to understand the functional role of genes,
the regulation of gene expression in various cell types and states, and how gene
expression is affected by various treatments and diseases.
Epigenetics refers to the study of variations in an individual’s phenotype, due to
differences in genetic expression, but which occur without changes in DNA
sequence. These sources of variation include the addition of certain chemical
groups, such as methyl groups, to DNA.
Copy number variation (CNV) refers to differences in the number of copies of
large stretches of DNA among individuals, differences that are caused by gains,
losses, and duplications of large chunks of DNA.
6. It has been over two decades since Stunkard and colleagues provided the first
evidence for a genetic component to obesity that the research community found
overwhelmingly compelling. Since then, we have: 1) further refined the
heritability of adiposity and shown that it is quite substantial, complex, and nonadditive; 2) identified literally scores of specific genes in animal models that can
unequivocally induce or reduce adiposity as well as alter other obesity-related
phenotypes; and 3) found several regions of the human genome that appear to
harbor genes increasing the risk of obesity. Most recently, we have perhaps the
first truly convincing report of an association of a specific genotype with
common obesity in humans and have since identified 22 more such associations.
7. One recently developed idea is that environmentally acquired alterations in
adiposity may be transmitted to generations beyond the parents’ immediate
offspring, due to what are termed epigenetic factors. This proposes that
environmental signals may be passed to grandchildren and subsequent
generations through effects on the genome, even if those generations did not
experience the original signal.
Understanding Obesity: Biological, Psychological and Cultural Influences. Edited by Sharon Akabas, Sally Ann Lederman
and Barbara J. Moore. © 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.