Transcript ************d

Human Genetics
Concepts and Applications
Tenth Edition
RICKI LEWIS
7
Biol 4355 - Genética
Humana
Capítulo 7 –
Rasgos
Multifactorial
Multifactoriales
Traits
UPR
– Aguadilla
JA Cardé, PhDPowerPoint
Lecture Outlines
Prepared by Johnny El-Rady, University of South Florida
®
Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display
Objetives
•
•
To consider characteristics that represent
input from many genes (multifactorial)
To review the tools used to study
multifactorial traits
2
Genes, Environment and Traits
Few, if any, genes act alone
Environmental factors and other genes may
modify expression
Traits can be described as
- Mendelian = Caused by a single gene
- Polygenic = Caused by multiple genes
Both can be multifactorial or complex due
to an interaction between genes and the
environment (epigenesis)
3
Genes, Environment and Traits
Single-gene traits are discrete or qualitative
- Often produce an “all-or-none” effect
Polygenic traits produce a continuously
varying phenotype
- Also called quantitative traits
- DNA sequences involved are termed
quantitative trait loci (QTLs)
4
Genes, Environment and Traits
Figure 7.1
5
Polygenic Traits
Are influenced by interaction of genes and
by the environment
Examples:
- Height
- Skin color
- Body weight
- Fingerprint patterns
- Behavioral traits
6
Polygenic Traits
Individual genes follow Mendel’s laws, but
their expression is hard to predict
Effect of genes is additive or synergistic
- However, input of genes is not
necessarily identical
The frequency of distribution of phenotypes
forms a bell-shaped curve!
7
Fingerprint Patterns
Dermatoglyphics is the study of fingerprints
The number of ridges is largely determined
by genes and prenatal contact with the
amniotic sac
The average total ridge count is 145 in a
male and 126 in a female
Abnormal numbers in Down Syndrome
8
Fingerprint Patterns
Figure 7.2
9
Height
The difference in height between the two sets
of students is attributed to improved diet and
better overall health
- 1920 height max = 5’9”
- 1997 height max = 6’5”
Genome-wide association studies have
identified dozens of genes that affect height
- Also, certain SNPs patterns are seen in
individuals with periods of rapid height
increase
10
1920 height max = 5’9”
Figure 7.3
Height
1920 height max = 6’5”
11
Skin Color
•
•
•
Melanin protects against DNA damage
from UV radiation
Exposure to the sun increases melanin
synthesis
All have same number of melanocytes per
unit area of skin
- However, we differ in melanosome
number, size and density distribution
12
Skin Color
Figure 7.4 – Modelo de 3 genes con dos alelos cada uno, para color de piel . Se
sortean de multiples formas dando mutiples tonos de color. (Gemelas, padre aleman
madre jamaiquina)
13
Skin Color
The definition of race based largely on skin
color is a social construct more than a
biological concept
Skin color is NOT a reliable indicator of
ancestry
- Overall, 93% of varying inherited traits are
no more common in people of one skin
color than any other
14
Summary
Polygenic Traits
- Determined by more than one gen and vary
continuously in expression
Multifactorial Traits
- Determined by a combination of a gene, or genes
and the environment
- A bell curve describes the distribution of
phenotypic classes of a polygenic trait.
15
Investigating Multifactorial Traits
Empiric risk - measures or predict the likelihood that
a trait will recur based on incidence in specific
population
- ethnic group, community, families with CF
Incidence- the rate at which a certain new event
occurs in a population during some period of time
Prevalence - number of individuals who have a
particular trait at a specific time (ie. during a year)
16
Empiric Risk
•
•
•
•
Is not a calculation
It is a population statistic based in observations
It will increase with:
- the severity of the disorder
- the number of affected individuals in a family
- how close (consanguinity) is the individual to
the affected individual
Ex: cleft lip
17
Investigating Multifactorial Traits
•
•
Cleft lip is more likely in a
person who has a relative with
the condition
The closer the relationship
between two individuals, one
of them having the condition,
the greater the probability that
the second individual has the
trait. They share more genes.
Figure 7.5
18
Investigating Multifactorial Traits
Table 7.2
19
Heritability (H)
Estimates the proportion of the phenotypic variation in a
population due to genetic differences
What factors contribute to the observed variation in a trait?
Figure 7.6
20
Heritability (H)
H=1:variability
completely due to
gene action (lab rats)
- No environmental
variability: genetic
differences alone
determine
expression of a
trait
- H changes as
environment
changes.
- Winter months vs21
Summer months
University of Puerto Rico
Intercampus Doctoral Program in Biology
Effects of Plasticizers on Vtg Synthtesis
BPA
(μg)
250
375 500 1000
C+
Vtg
169
153
116
Alb
1
2
3
4
5
6
Anti S1
(Vtg)
University of Puerto Rico
Intercampus Doctoral Program in Biology
Effect of Methoxychlor on Vtg Synthesis
Mtx 70 μg
C-
C+
Vtg
169
153
116
Alb
1
2
3
4
5
6
7
8
9
Anti S1
(Vtg)
University of Puerto Rico
Intercampus Doctoral Program in Biology
Dose Response Experiments
Endocrine Disrupting Chemicals
Metoxychlor
(Mtx)
Dose Vtg
(µg)
+
Bisphenyl A
(BPA)
Vtg
-
Dose
(µg)
Diethylstilbestrol
(DES)
Vtg Vtg Dose Vtg
+
(µg)
+
Vtg
-
70
4
3
375
2
5
0.3a
6
0
140
5
2
500
1
6
3.0
7
0
280
5
2
1000a
1
3
30a
5
1
(a) Dead animals.
Heritability (H)
Researchers use several statistical methods
to estimate heritability
One way is to compare the proportion of
people sharing a trait to the proportion
predicted to share the trait
The expected proportion is derived by
knowing the blood relationships of the
individuals and using the C of R
25
Coefficients of Relatedness
The proportion of genes shared between two
people related in a certain way
Table 7.4
26
Adopted Individuals
Similarities between adopted people and
adopted parents reflect mostly
environmental influences
Similarities between adoptees and their
biological parents reflect mostly genetic
influences
Therefore, information on both sets of
parents can reveal how heredity and the
environment both contribute to a trait
27
Twins
Twin studies have largely replaced adoption
methods
Concordance measures the frequency of
expression of a trait in both members of
monozygotic (MZ) or dizygotic (DZ) twins
- Twins who differ in a trait are said to be
discordant for it
For a trait largely determined by genes,
concordance is higher for MZ than DZ twins
28
Twins
Table 7.4
Tuberculosis?? Vs Susceptibilidad
29
Separating Genetic and
Environmental Influences
Dizygotic twins = Shared environment and
50% of genes
Monozygotic twins = Identical genotype
and shared environment
Twins raised apart = Shared genotype but
not environment
Adopted individuals = Shared environment
but not genes
30
Twins
Figure 7.8
31
Genome-Wide Association Studies
Older techniques search for known gene
variants, typically in only a few people
Sequencing of the human genome and the
HapMap project (which identifies SNPs)
have led to a new tool
Genome-wide association studies seek
correlations between SNP patterns and
phenotypes in large groups of individuals
32
Genome-wide Association Studies
(GWAS)
Studies to identify common variants behind a
particular phenotype
Study to identify genetic associations with
observables traits (Blood pressure/weight)
Genetic markers: used to follow variations,
across the genome, form patterns
compared between groups with a disease
33
underexpressed
Table 7.5
34
SNPs
SNPs (single nucleotide polymorphisms) are
sites in a genome where the DNA base
varies in at least 1% of the population
In these studies, SNPs span the genome,
rather than define a single gene
- A SNP can be anywhere among our
roughly 3.2 billion base pairs
35
SNPs
Figure 7.9
36
Genome-wide association studies seek SNPs that
are shared with much greater frequency among
individuals with the same trait than among others
Figure 7.10
37
A Step-wise Approach to Gene Discovery
Figure 7.11
38
Study Designs
In a cohort study, researchers follow a
large group of individuals over time and
measure many aspects of their health
In a case-control study, pairs of individuals
from different groups are matched so that
they share as many demographics
characteristics as possible
- SNP differences are then associated with
the presence or absence of the disorder
39
Study Designs
The “affected sibling pair” strategy scans
genomes of siblings for SNPs shared by
those with the condition, but not by those
who don’t have it
Homozygosity mapping is performed on
families that are consaguineous
- The children in this case are more likely
to inherit two copies of the mutation
40
Limitations of Genome-Wide
Association Studies
1) They include so many data points and so are
prone to error
2) They reveal associations between two types
of information, not causes
3) Bias can be introduced in the way the patient
population is selected
4) Their accuracy is affected by complicating
factors, such as phenocopy and epistasis
5) They may miss extremely rare SNPs
41
Table 7.6
42
Asignado: Body Weight
Body weight is a multifactorial trait that
reflects energy balance
About 30% of all adults in the US are obese,
and another 35% are overweight
Scientific studies use a measurement called
body mass index (BMI)
= weight (kg)/height2 (m2)
43
Body Mass Index (BMI)
Figure 7.12
44
Body Weight
Studies on adopted individuals and twins
indicate a heritability of 75% for obesity
Lifestyle, including diet and exercise, are
environmental components impacting
weight
Genes influence hunger and metabolism
45
Leptin and Associated Proteins
Leptin is a protein hormone produced by fat
cells
- Acts on the brain to decrease appetite
Ghrelin is a peptide hormone produced in
the stomach
- Responds to hunger by increasing
appetite
These and other hormones are important for
general weight regulation
46
Leptin and Associated Proteins
Table 7.8
47