Download Class 34 Genes and Behavior, continued Obesity Comparative

Class 34
Genes and Behavior, continued
Obesity
Comparative Genomics
Learning Goals
•  Describe some of the complexities of understanding multifactorial
syndromes
•  Explain how the brain senses and regulates "satiation" and food intake,
and how leptin is thought to be involved
•  Compare the effects of different kinds of mutations (alleles) in the
same behavior (such as obesity)
•  Discuss what can be learned from studying model systems and
comparing genomes among organisms
Obesity
About 1/3 of Americans are considered obese (more
than 20% over their ideal body weight)
Body weight is often reported as an
index called BMI: Body Mass Index
weight:height relationship
Heritability for BMI is .55
There are more than 50
regions in the genome associated with
how much we eat, how we use
calories and how fat is distributed.
Usually, it is a combination of all
these factors that leads to obesity
(not just overeating).
Obesity often leads to diabetes and heart disease.
Along with being overweight or obese, the following conditions will put a
person at even greater risk for heart disease and other conditions:
Risk Factors
High blood pressure (hypertension)
High LDL cholesterol ("bad" cholesterol)
Low HDL cholesterol ("good" cholesterol)
High triglycerides
High blood glucose (sugar)
Family history of premature heart disease
Physical inactivity
Cigarette smoking
For people who are considered obese (BMI greater than or equal to 30) or
those who are overweight (BMI of 25 to 29.9) and have two or more risk
factors, it is recommended that you lose weight. Even a small weight loss
(between 5 and 10 percent of your current weight) will help lower your risk
of developing diseases associated with obesity.
h"ps://www.nhlbi.nih.gov/health •  Obesity: some estimates of up to 80% heritability.
•  Genetic components: genes influencing hunger,
metabolism, storage of fat, production of hormones
•  Environmental components: diet and exercise
Body weight is incredibly stable: most people report
that dieting is not successful—people seem to have a
“set” weight that their body returns to
So, what factors and genes impact the behavior of
overeating, leading to obesity?
One candidate gene: Leptin
•  Leptin is a hormone that signals sufficient calorie intake.
•  Leptin travels in bloodstream and is bound by leptin receptors in
the brain; this affects desire to eat
Hypothalamus
Leptin
Regulation of fat conversion;
rate of energy consumption
Fat cells
When you haven’t eaten in a while, your leptin levels are low
This causes you to feel hungry
When you eat, your leptin levels rise, and your feeling of hunger falls
When you haven’t eaten in a while, your leptin levels are low, causing you to feel hungry
Hypothalamus
Leptin
Regulation of fat conversion;
rate of energy consumption
Fat cells
Given this information, what is the normal role of leptin in the
human body?
a. helps the brain decide to stop eating
b. helps the brain decide to keep eating
c. accumulates in fat cells
d. prevents cells from accumulating fat
The discovery of an obese mouse jump-started studies on genetic
components of heredity
Obese mouse: mutation in Leptin gene
Normal mouse
What kind of mutation in the Leptin gene causes this phenotype?
a.  One that leads to low or no leptin protein being present
b.  One that leads to more leptin protein being produced
When a gene is affected so it can no longer function, the
phenotype that results is a clue to the normal function of the
gene; in other words, leptin normally BLOCKS desire to eat
Mutations in a gene can lead to
Less of a gene product, no gene product, or product
with reduced function
What else?
•  Nothing (silent mutation)
•  More of a gene product, or product has new
activity
•  Change in expression (protein expressed at a
lower level, at the wrong time, in the wrong place)
Example of expression differences:
-two cells might both make a certain kind of
protein but one generates such a protein at a
much higher level
-protein expressed at different time
Where is such a mutation likely to be located
within a DNA sequence if it has this effect on
the protein?
a. An exon
b. An intron
c. A regulatory sequence (like a promoter region)
Story of leptin mutations in humans
People with leptin mutations that cause an
absence or very low levels of leptin are
hungry all the time
“At the age of four months the children
became possessed by a voracious hunger,
similar to experiences reported by people
who were starving.
…at first the parents complied with their
children’s demands. Eventually, though, they
took the doctor’s advice and padlocked the
cupboard door. The children scavenged
through the trash for soggy French fries and
gnawed frozen fish sticks from the freezer.
There was no stopping them.”
-Ellen Ruppel Shell: The Hungry Gene
When the children were given leptin, they eventually reached a normal
weight (same child shown at age 3 , and at age 7 after treatment).
What kind of conclusion can you draw from this
particular study (treating an obese individual
with leptin lowered body fat)
a. low leptin levels are correlated with obesity
b. low leptin levels can cause obesity
For these particular individuals just discussed, a complete absence of
Leptin did likely cause obesity, since treatment with
Leptin “cured” them.
However, in general, very few behavioral studies are able to show
cause and effect!
Furthermore, most people who are obese do NOT have leptin
mutations!
Despite the promise of the previous studies,
only about 10% of all cases of obesity are due to
leptin deficiency
Some obese people produce
normal levels of leptin.
Hypothalamus
Some obese people appear
unaffected by changes in
leptin.
What other genes might we
consider in studying the role of
leptin in obesity?
•  Leptin receptor
•  Proteins involved in
regulation of hypothalamus
activity
•  Proteins involved in
metabolism
•  Proteins that interact with
leptin
Leptin
Regulation of fat conversion;
rate of energy consumption
Fat cells
Obesity and Diabetes
Of the people diagnosed with type II diabetes, about 80
to 90 percent are also diagnosed as obese.
International Diabetes Foundation (IDF): “Diabetes and
obesity are the biggest public health challenge of the
21st century.”
As of 1999, diabetes affected 16 million (six
percent) of Americans – an increase of 40 percent in
just ten years.
Insulin is a hormone, produced by cells in the
pancreas: it regulates carbohydrate and fat
metabolism. Insulin is required for muscle and
fat tissue to absorb glucose from the blood.
In type II diabetes (usually acquired rather than inherited):
•  body makes enough insulin, but cells do not respond well to the insulin
•  different from type I diabetes, in which insulin is not produced
What could cause this?
A.  Excess of nutrients leads to decrease in number of insulin receptors
B.  Excess of nutrients leads to increase in number of insulin receptors
C.  Excess of nutrients leads to increase in insulin production
D.  Excess of nutrients leads to decrease in insulin production
Decrease in insulin receptors translates to insulin resistance and to
persistently high concentrations of glucose.
Mice with diabetes (type 1) treated with
leptin and insulin improved more than
those treated with insulin alone
Their blood sugar levels did not fluctuate
as much, cholesterol levels decreased, and
less body fat formed
So leptin may regulate use of insulin
Ways to explore and identify other genes or other behaviors that
might be correlated with obesity:
•  Do Genome Wide Association Studies
•  Explore how genes involved in addiction may be related to
overeating and obesity
•  Measure which neurons in the brain are active during or just
after food intake; use this information to develop drug targets
Comparative Genomics
In comparing genomes of modern species,
scientists
•  infer evolutionary relationships from DNA
sequences in different organisms
•  when we see similarities in sequences, and
the proteins they code for, it suggests
that these sequences were conserved over
time
•  these sequences likely have vital functions!
Comparing Genes and Genomes among different organisms
•  Similarities in DNA sequences among species can be assessed at
several levels:
• 
- Single gene; chromosome segment; a full chromosome;
mitochondrial DNA; or entire genome
•  The same mutation can cause similar effects in different species
• 
- People with Waardenburg syndrome have white forelocks, widespaced light-colored eyes, and hearing loss
•  This suggests the gene and its function are conserved
•  HOX gene mutation
causes synpolydactyly
Mutation in myostatin causes
“double muscling”
Comparing DNA from different organisms
Figure 16.12
Figure 16.14
Say you are comparing the DNA, RNA and amino
acid sequences for the gene that when mutated
results in Waardenburg sydrome and in cats,
mice and people. When you compare sequences
in these three organisms, you should see the
most similarity between:
a.  DNA sequences
b.  RNA sequences
c.  Amino Acid sequences
d.  The three comparisons will be the same
Amino acid sequences
can potentially offer
quite meaningful
comparisons if
interested in subtle
differences in how
the protein functions
Table 16.3
Genetic Markers
Mitochondrial DNA (mtDNA)
-  Used to trace maternal lineage
-  Relatively abundant (multiple mitochondria per cell)
- Lack of DNA repair in mitochondria leads to a
faster mutation rate
Mitochondrial “Eve”
•  mtDNA sequences of indigenous peoples worldwide
were compared to determine the common ancestral
mtDNA sequence
•  Hypothesized ancestral woman lived approximately
170,000-200,000 years ago in Africa
•  This is remarkably close to the date of the Homo
sapiens idaltu fossils
Y chromosome markers
•  Only part of Y chromosome is similar
enough to X chromosome to recombine
•  Thus most of Y chromosome is intact
from generation to generation
•  One copy of Y per individual (only have
to consider one sequence)
Hatshepsut was a pharaoh who ruled Egypt more than
3000 years ago. In 2008 her mummy was found and
tentatively identified due to a distinctive tooth that
had been described in writings about her. Which of
the following lines of DNA evidence would have been
used to establish that Hashepsut was in fact an
ancestor of currently living people who claim to be part
of the royal line?
a.  Y chromosome markers
b.  Mitochondrial DNA
c.  SNP sequences
d.  B and C
e.  A and C