Genetic Heritability
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Transcript of Genetic Heritability
Genetic Heritability
Nusrat Jahan
New York City College of Technology
Tuesday, December 8, 2015
In genetics, heritability is the proportion of phenotypic variation in a population that is due to
genetic variation. Variation among individuals may be due to genetic and/or environmental factors.
Heritability analyses estimate the relative importance of variation in each of these factors. The Role of
Genetics in Disease Heritability, Risk, and Pathways of Pathogenesis in Human Autoimmunity is a
common factor in today’s life. Autoimmune diseases are characterized by their unique course of action
the body's loss of recognition and tolerance to itself. symptoms characteristically associated with common
autoimmune diseases (e.g. swelling, fatigue, increased rates of sickness, etc.) stem from the body's
overactive immune response. Some types of prevalent autoimmune disorders include systemic umps
erythematosus (SLE), a disease which causes inflammation of the joints, affects multiple organs, and can
immobilize its host, glomerulonephritis, a disease characterized by increased potassium in the blood
(hyperkalemia), unusual urine sedimentation or loss of flow (oliguria), and blood in the urine (hematuria),
and Wegener's granulomatosis, which is a sinonasal inflammatory disease that is similar to sarcoidosis.
[1, 2] According to an epidemiology study done in 2002, over 3225 people per 100,00 are afflicted with
an autoimmune disease. What's more alarming is that over 80% of this figure is female. [3] This suggests
that autoimmune diseases are relatively much more sexlinked than autosomal. A newer study confirms
that shutting down the IRAK1 gene, which is contained on the Xchromosome, shuts down SLE in an
animal model. [4] With recent advances in technology, autoimmune phenotypes can now be traced to
specific single nucleotide polymorphisms (SNPs) in the human genome using various phase haplotype
maps. [5] This work will evaluate the role of genetics in disease heritability, susceptibility to autoimmune
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diseases as a result of these SNPs, and various pathways of pathogenesis a disease might use to impact the
organism (human).
First, the role of genetics in disease heritability will be evaluated. In pedigree analysis, we know
that certain traits or diseases may be autosomal, xlinked, or ylinked. The field of behavior genetics is
rapidly expanding. The practice of altering genes in mice and observing the effects is very common.
Because of this it would be appropriate to adopt specific tests which will demonstrate the behavioral
phenotype of the organism.
In testing for the effects of genetic alteration it must first be ascertained that all of the necessary
genotypes are represented. These include homozygous and heterozygous mice and wild type mice with no
genetic alterations as controls. If significant differences are found between male and female mice the two
sexes must be evaluated on their own. Care must also be taken in selecting the right strain of mice. This is
because it has been found that in the strains that are usually used for testing some behaviors are noted to
be aberrant and the unusual behavior in these genes might lead to the misinterpretation of the studied
mutation. Different approaches are used in order to make the interpretation of these results more accurate
in this sort of genetic background.
When evaluating the behavior of genetically altered mice it must be ascertained that the mice
don’t show any signs of aberrant behavior which would make further testing difficult or impossible.
Indices of general health are obtained by recording the mouse’s weight, temperature, and any abnormal
features. Neurological function is then assessed using different types of tests. The mouse is stimulated to
see if it reacts normally to various different types of stimuli. Reflexes are measured by seeing how the
animal reacts to a moving surface, light, and touch. The mouse is then observed in an area resembling an
open field where its movements are recorded. Motor coordination is measure by placing it on a rotating
rod and seeing how well it maintains its balance. This is also measured by recording its footprints in ink
and measuring their pattern and the distance between them. The hearing ability of mice is also measured.
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These tests can help demonstrate the behavioral paradigms for the animal that is being studied. In
some cases a deficit in motor or neurological function might make it impossible to run any further tests
since almost all behavioral tests require certain basic functions such as locomotion. Sometimes the tests
will have to be altered in order to effectively study the behavioral phenotype of the mice because of
deficits in their functioning. These tests can also serve to demonstrate behavioral phenotypes that might
warrant further study.
Mice that are genetically altered are studied for different reason. Some are studied so as to try to
find the genetic basis for human diseases. Defining the genetic basis for diseases with known behavioral
phenotypes can be used to help develop treatment for the disease. Some studies are conducted to test
hypothesis about the behavioral phenotype of a given gene. For these studies specific behavioral
paradigms should be chosen that have been studied previously and the results should undergo statistical
analyses. Then there are studies conducted to find the effect of an altered gene when no hypotheses has
been formed about its effect.
Estimating Trait Heritability: Genetic variation in a population can result from a variety of
things. What are the ways we can estimate trait heritability? A central question in biology is whether
observed variation in a particular trait is due to environmental or to biological factors, sometimes
popularly expressed as the "nature versus nurture" debate. Heritability is a concept that summarizes how
much of the variation in a trait is due to variation in genetic factors. Often, this term is used in reference to
the resemblance between parents and their offspring. In this context, high heritability implies a strong
resemblance between parents and offspring with regard to a specific trait, while low heritability implies a
low level of resemblance.
Quantifying Heritability: Phenotypes that vary between the individuals in a population do so
because of both environmental factors and the genes that influence traits, as well as various interactions
between genes and environmental factors. Unless they are genetically identical (e.g., monozygotic twins
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in humans, inbred lines in experimental populations, or clones), the individuals in a population tend to
vary in the genotypes they have at the loci affecting particular traits. The combined effect of all loci,
including possible allelic interactions within loci (dominance) and between loci (epistasis), is the
genotypic value. This value creates genetic variation in a population when it varies between individuals.
In fact, heritability is formally defined as the proportion of phenotypic variation (VP) that is due to
variation in genetic values (VG).
Genotypes or genotypic values are not passed on from parents to progeny; rather, it is the alleles
at the loci that influence the traits that are passed on. Therefore, to predict the average genotypic value of
progeny and their predicted average phenotype, investigators need to know the effect of alleles in the
population rather than the effect of a genotype. The effect of a particular allele on a trait depends on the
allele's frequency in the population and the effect of each genotype that includes the allele. This is
sometimes termed the average effect of an allele. The additive genetic value of an individual, called the
breeding value, is the sum of the average effects of all the alleles the individual carries (Falconer &
Mackay, 1996). According to the principles of Mendelian segregation, one allele from each locus is
present in each gamete, and in this way, additive genetic values are passed on from parents to progeny.
Indeed, because each offspring receives a different set of alleles from its parents, half of the additive
genetic variance in the population occurs within families.
Broadsense heritability, defined as H2 = VG/VP, captures the proportion of phenotypic variation
due to genetic values that may include effects due to dominance and epistasis. On the other hand,
narrowsense heritability, h2 = VA/VP, captures only that proportion of genetic variation that is due to
additive genetic values (VA). For definitions and decomposition of components of variation, you can read
more about phenotypic variance. Note that often, no distinction is made between broad and narrowsense
heritability; however, narrowsense h2 is most important in animal and plant selection programs, because
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response to artificial (and natural) selection depends on additive genetic variance. Moreover, resemblance
between relatives is mostly driven by additive genetic variance (Hill et al., 2008).
Given its definition as a ratio of variance components, the value of heritability always lies
between 0 and 1. For instance, for height in humans, narrowsense heritability is approximately 0.8
(Macgregor et al., 2006). For traits associated with fitness in natural populations, heritability is typically
0.1–0.2 (Visscher et al., 2008).
Figure Detail: Heritability estimation. Low (panel a) and high (panel b) heritability can be
estimated from the regression (h2) of offspring phenotypic values vs. the average of parental phenotypic
values.
Heritability Estimation: Estimation of heritability in populations depends on the partitioning
of observed variation into components that reflect unobserved genetic and environmental factors. In other
words, researchers recognize that genetic and/or environmental variation exists, but they may not be in a
position to assess either directly. However, this does not prevent them from being able to estimate the
relative effects of both genes and environment on phenotype. Here, heritability can be estimated from
empirical data on the observed and expected resemblance between relatives. The expected resemblance
between relatives depends on assumptions regarding a trait's underlying environmental and genetic
causes. Traditionally, heritability was estimated from simple, often balanced, designs, such as the
correlation of offspring and parental phenotypes, the correlation of full or half siblings, and the difference
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in the correlation of monozygotic (MZ) and dizygotic (DZ) twin pairs. Heritability can also be estimated
from the ratio of the observed selection response (R) to the observed selection differential (S) in artificial
selection experiments. This relationship is summarized in the "breeder's equation," R = h2S.
In given Figure, examples are given of a scatterplot of progeny phenotypes (yaxis) and the
average of two parental phenotypes (xaxis), for traits with high (0.9) and low (0.1) heritability. The
straight line is the bestfit linear relationship between y and x, obtained from a statistical technique called
linear regression. The slope of the regression line is an estimate of narrowsense heritability. For the high
heritability of 0.9 (Figure 1b), there still is a lot of variation around the regression line, because the
correlation between offspring phenotype and midparent value is √(½)h2, which is only 0.64 for h2 = 0.9.
Even when the heritability is 1.0 (i.e., there is no environmental variation), the phenotypes of offspring
and parents are not identical because of random segregation of alleles from parents to progeny. This
explains, for example, why human siblings can vary considerably in height, despite the heritability of
height being very large.
When phenotypic measures are available on individuals with a mixture of relationships, both
within and across multiple generations, or when the design is unbalanced (e.g., there are unequal numbers
of observations per family), estimates of additive genetic variance and environmental components are
most efficiently calculated via statistical methods that use all data simultaneously and take account of the
exact properties of the data. Such methods are iterative and computationally more intensive than estimates
of heritability that are based upon regression or correlation coefficients.
Estimating Heritability (Caveats): When estimating heritability from the observed and
expected resemblance between relatives, a model is necessary to specify the expected resemblance in
terms of genetic and environmental factors. Sometimes this model is straightforward; for example, it may
posit that the observed resemblance between halfsibling dairy cows on different farms is due solely to
additive genetic factors inherited from the common parent. In other cases, a model's assumptions may be
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open to questioning. For example, in human twin analysis, it is usually assumed that the resemblance
between monozygotic and dizygotic twin pairs due to shared environment is the same.
Recently, new methods that exploit the use of genetic marker data have been proposed and
applied to estimate heritability essentially free of such assumptions regarding the nature of
betweenfamily variation (Visscher et al., 2006). These methods are based upon the correlation between
phenotypic and genetic similarity within families. They exploit the fact that there is variation in identity
(defined here as the proportion of the genome that is shared identicalbydescent) between pairs of
individuals that have the same expected value and that this variation can be measured with genetic
markers. Variation in identity arises because of the random segregation of chromosomes during meiosis.
For full siblings in humans, the mean identity is 50%, with a standard deviation of approximately 4%.
Hence, some full siblings share only 40% of their genome by descent, while others share 60%. If those
siblings who share more of their genome than average are phenotypically more similar to each other than
those siblings who share less than average, then this similarity is most likely due to genetic factors. This
assumption was the basis of a study by Visscher et al. (2006), who estimated a narrowsense heritability
of height in humans of 0.8 using pairs of full siblings, without making any assumption about the variation
between families.
Heritability Is Not Necessarily Constant: Interestingly, heritabilities are not constant. For
example, estimates of heritability for first lactation milk yield in dairy cattle nearly doubled from
approximately 25% in the 1970s to roughly 40% in recent times. Heritability can change over time
because the variance in genetic values can change, the variation due to environmental factors can change,
or the correlation between genes and environment can change. Genetic variance can change if allele
frequencies change (e.g., due to selection or inbreeding), if new variants come into the population (e.g.,
by migration or mutation), or if existing variants only contribute to genetic variance following a change in
genetic background or the environment. The same trait measured over an individual's lifetime may have
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different genetic and environmental effects influencing it, such that the variances become a function of
age. For example, variance in weight at birth is influenced by maternal uterine environment, and variance
in weight at weaning depends on maternal milk production, but variance of mature adult weight is
unlikely to be influenced by maternal factors, which themselves have both a genetic and environmental
component. Heritabilities may be manipulated by changing thevariance contributed by the environment.
Empirical evidence for morphometric traits suggests lower heritabilities in poorer environments, but not
for traits more closely related to fitness (Charmantier & Garant, 2005). Understanding how heritability
changes with environmental stressors is important for understanding evolutionary forces in natural
populations (Charmantier & Garant, 2005).
Misconceptions of the Heritability Concept: There are a number of common
misconceptions on the exact meaning and interpretation of heritability (Visscher et. al., 2008). Heritability
is not the proportion of a phenotype that is genetic, but rather the proportion of phenotypic variance that is
due to genetic factors. Heritability is a population parameter and, therefore, it depends on
populationspecific factors, such as allele frequencies, the effects of gene variants, and variation due to
environmental factors. It does not necessarily predict the value of heritability in other populations (or
other species). Nevertheless, it is surprising how constant heritabilities are across populations and species
(Visscher et. al., 2008).
Applications of heritability estimation are broad and cross a range of disciplines, from
evolutionary biology to agriculture to human medicine. In humans, estimation of heritability has been
applied to diseases and behavioral phenotypes (e.g., IQ), and it has helped establish that a substantial
proportion of variation in risk for many disorders, like schizophrenia, autism, and attention
deficit/hyperactivity disorder, is genetic in origin.
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References:
Charmantier, A., & Garant, D. Environmental quality and evolutionary potential: Lessons from
wild populations. Proceedings of the Royal Society, Biological Sciences 272, 1415–1425 (2005)
Falconer, D. S., & Mackay, T. F. C. Introduction to Quantitative Genetics (Harlow, UK,
Longman, 1996)
Hill, W. G., et al. Data and theory point to mainly additive genetic variance for complex traits.
PLoS Genetics 4, e1000008 (2008)
Macgregor, S., et al. Bias, precision and heritability of selfreported and clinically measured
height in Australian twins. Human Genetics 120, 571–580 (2006)
Visscher, P. M., et al. Assumptionfree estimation of heritability from genomewide
identitybydescent sharing between full siblings. Public Library of Science Genetics 2, e41
(2006)
Heritability in the genomics era—Concepts and misconceptions. Nature Reviews Genetics 9,
255–266 (2008) Article Linked
Heritability