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