Chromosomes contain the recipe for making a living thing. They are found in almost every cell’s nucleus and are made from strands of DNA (deoxyribonucleic acid). Segments of DNA called "genes" are the ingredients. Each gene adds a specific protein to the recipe. Proteins build, regulate and maintain your body. For instance, they build bones, enable muscles to move, control digestion, and keep your heart beating.

Most of our cells contain 46 chromosomes. Sperm and egg cells contain only 23 chromosomes. When the sperm and egg cells unite, the resulting fetus inherits half of its DNA recipe from its mother and half from its father.

Two of these 46 chromosomes determine the sex of a person. A girl inherits two X-chromosomes, one from her mother and one from her father. A boy inherits one X-chromosome from his mother and a small Y-chromosome from his father.

A trait, as related to genetics, is a specific characteristic of an individual. Traits can be determined by genes, environmental factors or by a combination of both. Traits can be qualitative (such as eye color) or quantitative (such as height or blood pressure). A given trait is part of an individual’s overall phenotype.

Trait. When you think of the word traits, you might think of personality traits like compassionate or a good sense of humor. In genetics, traits are characteristics about humans and other living organisms that can be described or measured. Traits can be physical or behavioral. Researchers and clinicians are interested in what causes people to have certain traits and not others, especially when those traits give us clues about causes and treatments of illness. When someone has a combination of a few particular traits, that might give us clues about how to diagnose a medical condition. And we can compare those traits to similar combinations of traits in other people to study how different diseases might be related to each other.

Sara Chandros Hull, Ph.D., Deputy Director, Office of the Scientific Director

The Austrian monk Gregor Mendel (1822-1884) was the first person to describe how traits are inherited from generation to generation. He studied how pea plants inherited traits such as color and smoothness, and discovered that traits are inherited from parents in certain patterns. Not until the 20th century did other scientists take his ideas further. Mendel is considered to be the father of genetics, although his work was relatively unappreciated until the early 20th century.

A gene can exist in many different forms, called alleles. For example, let’s say that there is one gene which determines the color of your hair. That one gene may have many forms, or alleles: black hair, brown hair, auburn hair, red hair, blond hair, etc. You inherit one allele for each gene from your mother and one from your father.

Each of the two alleles you inherit for a gene each may be strong ("dominant") or weak ("recessive"). When an allele is dominant, it means that the physical characteristic ("trait") it codes for usually is expressed, or shown, in the living organism. You need only one dominant allele to express a dominant trait. You need two recessive alleles to show a recessive form of a trait.

Did you know that at the base-pair level your genome is 99.9 percent the same as all of the humans around you - but in that 0.1 percent difference are many of the things that make you unique? We have learned that people's genomes differ from each other in all sorts of ways. Those differences in your DNA help to determine what you look like and what your risk might be for various diseases. But your genome doesn't entirely define you.

Well before the completion of the Human Genome Project, researchers began developing tools to detect genomic differences between people. When scientists agreed to use the one "reference" human genome sequence generated by the Human Genome Project [see DNA Sequencing], it became easier to determine differences among people's genomes on a much larger scale. We have since learned that human genomes differ from one other in all sorts of ways: sometimes at a single base, and sometimes in chunks of thousands of bases. Even today, researchers are still discovering new types of variants within human genomes. Human genomic variation is particularly important because a very small set of these variants are linked to differences in various physical traits: height, weight, skin or eye color, type of earwax, and even specific genetic diseases.

Beauty in Diversity

Rick Guidotti built his career as a fashion photographer until he decided that he wanted to showcase beauty in a different way. Through his not-for-profit organization called Positive Exposure, he began taking beautiful photographs of children and adults with genetic conditions that we don't always see showcased in magazines or on billboards. Rick's work has highlighted the beauty in human diversity (much of it caused by genomic variation); you can see true joy in their online gallery, "The New Faces of Genetics And Beyond." Rick has gone on to create projects like FRAME (Faces Redefining the Art of Medical Education), which is designed to substitute the images of unsmiling children often used in the medical literature and text books with joyous photographs and fun short movies. As Rick says, medical students "are going to be better doctors, because they've seen these kids not in crisis. They've met these kids not in a clinical environment, but they've seen these kids as people."

The Human Genome Project has also led to a change in our understanding of human traits and how we teach them - one example is eye color. For many years, students were taught that one dominant gene controlled brown or blue eyes and that blue-eyed parents could not have brown-eyed children. Scientists knew that the blue-eyes trait was actually more complicated despite what was taught in schools, but technology developed during and after the Human Genome Project helped pinpoint the actual combination of genomic variants that determine eye color. In fact, at least ten genes each of which comes in several "flavors," contribute to eye color. It is the combination of these gene variants in a person's genome that produces the wonderful range of human eye colors. Other traits are even more complicated; for example, around 80 percent of a person's height is controlled by more than 700 genomic variants, each one having a very small influence.

Another area where our understanding of biology has greatly advanced is in the genomics of skin color. Unfortunately, for centuries, skin color has been used as the basis for discrimination against some populations, a consequence of the inaccurate concept of human races. We have always known that skin comes in a wide array of hues and tints. Thanks to the work of Dr. Sarah Tishkoff and her colleagues, we now also know that skin color has changed quite a bit over time, with mixing and matching occurring throughout different populations. Sarah and her team visited numerous different communities throughout Africa, working with them to study their genomes. Her work has shown that there are multiple genomic variants contributing to skin color: some make it lighter, some make it darker, and all of them originated in Africa. Throughout evolution, skin color has been affected by the environment. For example, Sarah's work supports the hypothesis that lighter skin in climates further away from the sun gave an individual a selective advantage (because their skin was able to make more vitamin D and avoid diseases like rickets). In contrast, darker skin color was helpful in climates with more sun (because the pigments in the skin help to prevent sun damage and skin cancer).

This new understanding of the importance of both genomics and the environment has led Sarah and other genetics researchers to call for medical studies to stop using skin color or race as a biological category. Instead, genomic testing for variants that influence traits that are deeper than skin can be used to understand how their genomes might influence their health.

We Are Still Learning

One of the most astonishing things that we have learned about human genomic variation is that we cannot always predict the effect of a given variant. Sometimes there are clear relationships, such as for red hair (the hair color of most redheads is due to one of three single-base changes in a particular gene). But a large study that started in 2012 has shown that each human is walking around with an average of 200 genes that are broken; for about 20 of those genes, both copies (one inherited from each parent) are not working, so there is a "loss-of-function." Surprisingly, in some people, one of those 20 doubly broken genes was previously thought to be responsible for a genetic disease. We would think a person with such a mutation should be sick, but for some reason they are not! Are they "genetic superheroes?" Or are they just more resilient to these genomic variants for reasons that we don't yet understand?

Another possibility is that they are "mosaic," meaning that they have "harmful" genomic variants in some tissues but not others. For example, Joseph Merrick, the subject of the book and movie "The Elephant Man," is thought to have had a disease called Proteus syndrome, which causes overgrowth of skin or other tissues. In 2011, a group showed that mutations occurred in the gene AKT1 in this syndrome. Each person with the syndrome does not look the same because they have different areas of skin overgrowth, and we now know this is because the genomic variant occurred in a different set of cells. Interestingly, the new abilities to sequence very small amounts of DNA have shown that we are all mosaics, and that the genome in one tissue is not always exactly the same as in another. This is a potential problem for diagnosis; since only the DNA in blood is typically sequenced, mosaic-like variations elsewhere in the body could be missed. Single-cell genome sequencing of neurons in our brains even suggests that one neuron might not be the same as the one right next to it!

Studying genomic variants can also point to surprising new ways for developing medications, such as happened with the gene PCSK9. Many research projects have shown that high blood cholesterol levels raise the risk of developing heart disease. We know that both genetics and environment/diet contribute to your cholesterol level, so scientists have been looking for specific genes that might play a bigger role. By looking at lots of people, researchers found that there are some individuals have unusual levels of cholesterol in their blood. These people have very low levels of "bad" cholesterol and a reduced risk for developing heart disease. Scientists searched through their genomes and found that they carry a rare loss-of-function mutation in a gene called PCSK9. It appears that mutations that inactivate the PCSK9-encoded protein make people resilient to any type of diet. Scientists immediately realized that if they could "break" this gene in people who have a good copy, they might be able to lower their cholesterol too. They soon designed a medication that inactivated the protein made by PCSK9. This could mimic the protection from bad cholesterol found in the rare people who inherited the mutated PCSK9. Trials of such new medications have now shown they can lower cholesterol and should prevent heart attacks or strokes. We are likely to see more medicines based on naturally occurring loss-of-function variants revealed by genome sequencing.

Athletic performance is a complex trait that is influenced by both genetic and environmental factors. Many physical traits help determine an individual’s athletic ability, primarily the strength of muscles used for movement (skeletal muscles) and the predominant type of fibers that compose them. Skeletal muscles are made up of two types of muscle fibers: slow-twitch fibers and fast-twitch fibers. Slow-twitch muscle fibers contract slowly but can work for a long time without tiring; these fibers enable endurance activities like long-distance running. Fast-twitch muscle fibers contract quickly but tire rapidly; these fibers are good for sprinting and other activities that require power or strength. Other traits related to athleticism include the maximum amount of oxygen the body can deliver to its tissues (aerobic capacity), muscle mass, height, flexibility, coordination, intellectual ability, and personality.

Studies focused on similarities and differences in athletic performance within families, including between twins, suggest that genetic factors underlie 30 to 80 percent of the differences among individuals in traits related to athletic performance. Many studies have investigated variations in specific genes thought to be involved in these traits, comparing athletes with nonathletes.

The best-studied genes associated with athletic performance are ACTN3 and ACE. These genes influence the fiber type that makes up muscles, and they have been linked to strength and endurance. The ACTN3 gene provides instructions for making a protein called alpha (α)-actinin-3, which is predominantly found in fast-twitch muscle fibers. A variant in this gene, called R577X, leads to production of an abnormally short α-actinin-3 protein that is quickly broken down. Some people have this variant in both copies of the gene; this genetic pattern (genotype) is referred to as 577XX. These individuals have a complete absence of α-actinin-3, which appears to reduce the proportion of fast-twitch muscle fibers and increase the proportion of slow-twitch fibers in the body. Some studies have found that the 577XX genotype is more common among high-performing endurance athletes (for example, cyclists and long-distance runners) than in the general population, while other studies have not supported these findings. The 577RR genotype is associated with a high proportion of fast-twitch fibers and is seen more commonly in athletes who rely on strength or speed, such as short-distance runners.

The ACE gene provides instructions for making a protein called angiotensin-converting enzyme, which converts a hormone called angiotensin I to another form called angiotensin II. Angiotensin II helps control blood pressure and may also influence skeletal muscle function, although this role is not completely understood. A variation in the ACE gene, called the ACE I/D polymorphism, alters activity of the gene. Individuals can have two copies of a version called the D allele, which is known as the DD pattern, two copies of a version called the I allele, known as the II pattern, or one copy of each version, called the ID pattern. Of the three patterns, DD is associated with the highest levels of angiotensin-converting enzyme. The DD pattern is thought to be related to a higher proportion of fast-twitch muscle fibers and greater speed.

Many other genes with diverse functions have been associated with athletic performance. Some are involved in the function of skeletal muscles, while others play roles in the production of energy for cells, communication between nerve cells, or other cellular processes.

Other studies have examined variations across the entire genomes (an approach called genome-wide association studies or GWAS) of elite athletes to determine whether specific areas of the genome are associated with athleticism. More than 150 different variations linked to athletic performance have been identified in these studies; however, most have been found in only one or a few studies, and the significance of most of these genetic changes have not been identified. It is likely that a large number of genes are involved, each of which makes only a small contribution to athletic performance.

Athletic performance is also strongly influenced by the environment. Factors such as the amount of support a person receives from family and coaches, economic and other circumstances that allow one to pursue the activity, availability of resources, and a person’s relative age compared to their peers all seem to play a role in athletic excellence. A person’s environment and genes influence each other, so it can be challenging to tease apart the effects of the environment from those of genetics. For example, if a child and his or her parent excel at a sport, is that similarity due to genetic factors passed down from parent to child, to similar environmental factors, or (most likely) to a combination of the two? It is clear that both environmental and genetic factors play a part in determining athletic ability.

Dimples—indentations on the cheeks—tend to occur in families, and this trait is assumed to be inherited. Dimples are usually considered a dominant genetic trait, which means that one copy of the altered gene in each cell is sufficient to cause dimples. However, some researchers say that there is no proof that dimples are inherited. Little research has been done to explore the genetics of dimples and it is not known which gene or genes may be involved.

A dimple is an anomaly of the muscle that causes a dent in the cheek, especially when the individual smiles. Some people have dimples in both cheeks, others in just one cheek. Babies are likely to have dimples caused by baby fat in their cheeks. When they lose their baby fat as they get older, their dimples disappear. Other children do not have them at birth but may develop them later in childhood. In some people, dimples last only until adolescence or young adulthood, while in others they are a lifetime trait.

Dimples that have a similar appearance can occur in successive generations of a family. For example, in one family, it was observed that the siblings, their father, uncles, grandfather, and great-grandfather all had similar-looking dimples in both cheeks. In other families, dimples may occur in a child but are not seen in more than one generation.

A person’s eye color results from pigmentation of a structure called the iris, which surrounds the small black hole in the center of the eye (the pupil) and helps control how much light can enter the eye. The color of the iris ranges on a continuum from very light blue to dark brown. Most of the time eye color is categorized as blue, green/hazel, or brown. Brown is the most frequent eye color worldwide. Lighter eye colors, such as blue and green, are found almost exclusively among people of European ancestry.

Eye color is determined by variations in a person’s genes. Most of the genes associated with eye color are involved in the production, transport, or storage of a pigment called melanin. Eye color is directly related to the amount and quality of melanin in the front layers of the iris. People with brown eyes have a large amount of melanin in the iris, while people with blue eyes have much less of this pigment.

A particular region on chromosome 15 plays a major role in eye color. Within this region, there are two genes located very close together: OCA2 and HERC2. The protein produced from the OCA2 gene, known as the P protein, is involved in the maturation of melanosomes, which are cellular structures that produce and store melanin. The P protein therefore plays a crucial role in the amount and quality of melanin that is present in the iris. Several common variations (polymorphisms) in the OCA2 gene reduce the amount of functional P protein that is produced. Less P protein means that less melanin is present in the iris, leading to blue eyes instead of brown in people with a polymorphism in this gene.

A region of the nearby HERC2 gene known as intron 86 contains a segment of DNA that controls the activity (expression) of the OCA2 gene, turning it on or off as needed. At least one polymorphism in this area of the HERC2 gene has been shown to reduce the expression of OCA2, which leads to less melanin in the iris and lighter-colored eyes.

Several other genes play smaller roles in determining eye color. Some of these genes are also involved in skin and hair coloring. Genes with reported roles in eye color include ASIP, IRF4, SLC24A4, SLC24A5, SLC45A2, TPCN2, TYR, and TYRP1. The effects of these genes likely combine with those of OCA2 and HERC2 to produce a continuum of eye colors in different people.

Researchers used to think that eye color was determined by a single gene and followed a simple inheritance pattern in which brown eyes were dominant to blue eyes. Under this model, it was believed that parents who both had blue eyes could not have a child with brown eyes. However, later studies showed that this model was too simplistic. Although it is uncommon, parents with blue eyes can have children with brown eyes. The inheritance of eye color is more complex than originally suspected because multiple genes are involved. While a child’s eye color can often be predicted by the eye colors of his or her parents and other relatives, genetic variations sometimes produce unexpected results.

Several disorders that affect eye color have been described. Ocular albinism is characterized by severely reduced pigmentation of the iris, which causes very light-colored eyes and significant problems with vision. Another condition called oculocutaneous albinism affects the pigmentation of the skin and hair in addition to the eyes. Affected individuals tend to have very light-colored irises, fair skin, and white or light-colored hair. Both ocular albinism and oculocutaneous albinism result from mutations in genes involved in the production and storage of melanin. Another condition called heterochromia is characterized by different-colored eyes in the same individual. Heterochromia can be caused by genetic changes or by a problem during eye development, or it can be acquired as a result of a disease or injury to the eye.

Each person’s fingerprints are unique, which is why they have long been used as a way to identify individuals. Surprisingly little is known about the factors that influence a person’s fingerprint patterns. Like many other complex traits, studies suggest that both genetic and environmental factors play a role.

A person’s fingerprints are based on the patterns of skin ridges (called dermatoglyphs) on the pads of the fingers. These ridges are also present on the toes, the palms of the hands, and the soles of the feet. Although the basic whorl, arch, and loop patterns may be similar, the details of the patterns are specific to each individual.

Dermatoglyphs develop before birth and remain the same throughout life. The ridges begin to develop during the third month of fetal development, and they are fully formed by the sixth month. The function of these ridges is not entirely clear, but they likely increase sensitivity to touch.

The basic size, shape, and spacing of dermatoglyphs appear to be influenced by genetic factors. Studies suggest that multiple genes are involved, so the inheritance pattern is not straightforward. Genes that control the development of the various layers of skin, as well as the muscles, fat, and blood vessels underneath the skin, may all play a role in determining the pattern of ridges. The finer details of the patterns of skin ridges are influenced by other factors during fetal development, including the environment inside the womb. These developmental factors cause each person’s dermatoglyphs to be different from everyone else’s. Even identical twins, who have the same DNA, have different fingerprints.

Few genes involved in dermatoglyph formation have been identified. Rare diseases characterized by abnormal or absent dermatoglyphs provide some clues as to their genetic basis. For example, a condition known as adermatoglyphia is characterized by an absence of dermatoglyphs, sometimes with other abnormalities of the skin. Adermatoglyphia is caused by mutations in a gene called SMARCAD1. Although this gene is clearly important for the formation of dermatoglyphs, its role in their development is unclear.

Hair color is determined by the amount of a pigment called melanin in hair. An abundance of one type of melanin, called eumelanin, gives people black or brown hair. An abundance of another pigment, called pheomelanin, gives people red hair.

The type and amount of melanin determines hair color

The type and amount of melanin in hair is determined by many genes, although little is known about most of them. The best-studied hair-color gene in humans is called MC1R. This gene provides instructions for making a protein called the melanocortin 1 receptor, which is involved in the pathway that produces melanin. The melanocortin 1 receptor controls which type of melanin is produced by melanocytes. When the receptor is turned on (activated), it triggers a series of chemical reactions inside melanocytes that stimulate these cells to make eumelanin. If the receptor is not activated or is blocked, melanocytes make pheomelanin instead of eumelanin. Many other genes also help to regulate this process. Most people have two functioning copies of the MC1R gene, one inherited from each parent. These individuals have black or brown hair, because of the high amount of eumelanin. It is estimated that more than 90 percent of people in the world have brown or black hair.

Some people have variations in one copy of the MC1R gene in each cell that causes the gene to be turned off (deactivated). This type of genetic change is described as loss-of-function. For these individuals, eumelanin production is lower, while pheomelanin production is higher, so they have strawberry blond, auburn, or red hair. In an even smaller percentage of people, both copies of the MC1Rgene in each cell have loss-of-function changes, and the melanin-production pathway produces only the pheomelanin pigment. The hair of these individuals is almost always very red. Even when the melanin-production pathway is making eumelanin, changes in other genes can reduce the amount of eumelanin produced. These changes lead to blond hair.

Hair color ranges across a wide spectrum of hues, from flaxen blond to coal black. Many genes other than MC1R play a role in determining shades of hair color by controlling levels of eumelanin and pheomelanin. Some of these genes, including ASIP, DTNBP1, GPR143, HPS3, KITLG, MLPH, MYO5A, MYO7A, OCA2, SLC45A2, SLC24A5, TYRP1, TYR, ERCC6, GNAS, HERC2, IRF4, OBSCN, SLC24A4, TPCN2, and MITF, are involved in the production of melanin in hair. Some of these genes are associated with gene transcription (which is the first step in protein production), DNA repair, the transport of substances (such as calcium) across cell membranes, or the structure of hair follicles. Several of these genes contribute to eye and skin color, but the exact role they play in determining hair color is unknown.

Hair color may change over time. Particularly in people of European descent, light hair color may darken as individuals grow older. For example, blond-haired children often have darker hair by the time they are teenagers. Researchers speculate that certain hair-pigment proteins are activated as children grow older, perhaps in response to hormonal changes that occur near puberty. Almost everyone’s hair will begin to turn gray as they age, although when it happens and to what extent is variable. Gray hair is partly hereditary and may vary by ethnic origin; it is also somewhat dependent on external factors such as stress. Hair becomes gray when the hair follicle loses its ability to make melanin, but exactly why that occurs is not clear.

Genetic factors appear to play a major role in determining hair texture—straight, wavy, or curly—and the thickness of individual strands of hair. Studies suggest that different genes influence hair texture and thickness in people of different ethnic backgrounds. For example, normal variations (polymorphisms) in two genes, EDAR and FGFR2, have been associated with differences in hair thickness in Asian populations. A polymorphism in another gene, TCHH, appears to be related to differences in hair texture in people of northern European ancestry. It is likely that many additional genes contribute to hair texture and thickness in various populations.

Several genetic syndromes are characterized by unusual hair texture. These syndromes are caused by mutations in genes that play roles in hair structure and stability, including genes associated with desmosomes (specialized cell structures that hold hair cells together), keratins (proteins that provide strength and resilience to hair strands), and chemical signaling pathways involving a molecule called lysophosphatidic acid (LPA), which promotes hair growth. Genetic syndromes that feature altered hair texture include:

• Autosomal recessive hypotrichosis (caused by mutations in the DSG4, LIPH, or LPAR6 gene)
• Keratoderma with woolly hair (caused by mutations in the JUP, DSP, DSC2, or KANK2 gene)
• Monilethrix (caused by mutations in the DSG4, KRT81, KRT83, or KRT86 gene)
• Uncombable hair syndrome (caused by mutations in the PADI3, TCHH, or TGM3 gene)

Researchers speculate that the genes associated with these disorders probably also contribute to normal variations in hair texture and thickness, although little is known about the roles these genes play in normal hair.

Factors other than genetics can also influence hair texture and thickness. Hormones, certain medications, and chemicals such as hair relaxers can alter the characteristics of a person’s hair. Hair texture and thickness can also change with age.

Like most aspects of human behavior, handedness is a complex trait that appears to be influenced by multiple factors, including genetics, environment, and chance.

Handedness, or hand preference, is the tendency to be more skilled and comfortable using one hand instead of the other for tasks such as writing and throwing a ball. Although the percentage varies by culture, in Western countries 85 to 90 percent of people are right-handed and 10 to 15 percent of people are left-handed. Mixed-handedness (preferring different hands for different tasks) and ambidextrousness (the ability to perform tasks equally well with either hand) are uncommon.

Hand preference begins to develop before birth. It becomes increasingly apparent in early childhood and tends to be consistent throughout life. However, little is known about its biological basis. Hand preference probably arises as part of the developmental process that differentiates the right and left sides of the body (called right-left asymmetry). More specifically, handedness appears to be related to differences between the right and left halves (hemispheres) of the brain. The right hemisphere controls movement on the left side of the body, while the left hemisphere controls movement on the right side of the body.

It was initially thought that a single gene controlled handedness. However, more recent studies suggest that multiple genes, perhaps up to 40, contribute to this trait. Each of these genes likely has a weak effect by itself, but together they play a significant role in establishing hand preference. Studies suggest that at least some of these genes help determine the overall right-left asymmetry of the body starting in the earliest stages of development.

So far, researchers have identified only a few of the many genes thought to influence handedness. For example, the PCSK6 gene has been associated with an increased likelihood of being right-handed in people with the psychiatric disorder schizophrenia. Another gene, LRRTM1, has been associated with an increased chance of being left-handed in people with dyslexia (a condition that causes difficulty with reading and spelling). It is unclear whether either of these genes is related to handedness in people without these conditions.

Studies suggest that other factors also contribute to handedness. The prenatal environment and cultural influences may play a role. Additionally, a person’s hand preference may be due partly to random variation among individuals.

Like many complex traits, handedness does not have a simple pattern of inheritance. Children of left-handed parents are more likely to be left-handed than are children of right-handed parents. However, because the overall chance of being left-handed is relatively low, most children of left-handed parents are right-handed. Identical twins are more likely than non-identical twins (or other siblings) to be either right-handed or left-handed, but many twins have opposite hand preferences.

Scientists estimate that about 80 percent of an individual’s height is determined by the DNA sequence variants they have inherited, but which genes these variants are in and what they do to affect height are only partially understood. Some rare gene mutations have dramatic effects on height (for example, variants in the FGFR3 gene cause achondroplasia, a rare condition characterized by short stature). For most individuals, though, height is controlled largely by a combination of genetic variants that each have more modest effects on height, plus a smaller contribution from environmental factors (such as nutrition). More than 700 such gene variants have been discovered and many more are expected to be identified. Some of these variants are in genes that directly or indirectly affect cartilage in growth plates, which are areas in the long bones of the legs and arms where new bone is produced, lengthening the bones as children grow. The function of many other height-associated genes remains unknown.

In addition to the FGFR3 gene, researchers have identified hundreds of other genes involved in rare disorders that have an extreme effect on height. These genes (and the conditions they are associated with) include FBN1 (acromicric dysplasia, geleophysic dysplasia, Marfan syndrome), GH1 (isolated growth hormone deficiency), EVC (Ellis-van Creveld syndrome, Weyers acrofacial dysostosis), and GPC3 (Simpson-Golabi-Behmel syndrome). By studying the dramatic effect that altered versions of these genes have on height, scientists hope to better understand the complex interactions among genes that contribute to normal height. Some genes, such as ACAN, contain rare variants that cause severe growth disorders, and also other variants with milder effects on height in individuals without a related health condition. Identifying other height genes, and variants with large or small effects, is an active area of genetic research.

Because height is determined by multiple gene variants (an inheritance pattern called polygenic inheritance), it is difficult to accurately predict how tall a child will be. The inheritance of these variants from one’s parents helps explain why children usually grow to be approximately as tall as their parents, but different combinations of variants can cause siblings to be of different heights. Height is influenced by other biological mechanisms (such as hormones) that may also be determined by genetics, although the roles of these mechanisms are not fully understood.

In addition to genetic and biological determinants, height is also influenced by environmental factors, including the nutritional status of the mother during pregnancy, whether she smoked, and her exposure to hazardous substances. A well-nourished, healthy, and active child is likely to be taller as an adult than will be a child with a poor diet, infectious diseases, or inadequate health care. Socioeconomic factors such as income, education, and occupation can also influence height. In some cases, ethnicity plays a role in adult height, but studies on immigrant families have shown that moving to a country with better access to nutritious food, healthcare, and employment opportunities can have a substantial influence on the height of the next generation; this suggests that some differences in height between ethnicities are explained by non-genetic factors.

Like most aspects of human behavior and cognition, intelligence is a complex trait that is influenced by both genetic and environmental factors.

Intelligence is challenging to study, in part because it can be defined and measured in different ways. Most definitions of intelligence include the ability to learn from experiences and adapt to changing environments. Elements of intelligence include the ability to reason, plan, solve problems, think abstractly, and understand complex ideas. Many studies rely on a measure of intelligence called the intelligence quotient (IQ).

Researchers have conducted many studies to look for genes that influence intelligence. Many of these studies have focused on similarities and differences in IQ within families, particularly looking at adopted children and twins. These studies suggest that genetic factors underlie about 50 percent of the difference in intelligence among individuals. Other studies have examined variations across the entire genomes of many people (an approach called genome-wide association studies or GWAS) to determine whether any specific areas of the genome are associated with IQ. These studies have not conclusively identified any genes that underlie differences in intelligence. It is likely that a large number of genes are involved, each of which makes only a small contribution to a person’s intelligence.

Intelligence is also strongly influenced by the environment. Factors related to a child’s home environment and parenting, education and availability of learning resources, and nutrition, among others, all contribute to intelligence. A person’s environment and genes influence each other, and it can be challenging to tease apart the effects of the environment from those of genetics. For example, if a child’s IQ is similar to that of his or her parents, is that similarity due to genetic factors passed down from parent to child, to shared environmental factors, or (most likely) to a combination of both? It is clear that both environmental and genetic factors play a part in determining intelligence.

The duration of human life (longevity) is influenced by genetics, the environment, and lifestyle. Environmental improvements beginning in the 1900s extended the average life span dramatically with significant improvements in the availability of food and clean water, better housing and living conditions, reduced exposure to infectious diseases, and access to medical care. Most significant were public health advances that reduced premature death by decreasing the risk of infant mortality, increasing the chances of surviving childhood, and avoiding infection and communicable disease. Now people in the United States live about 80 years on average, but some individuals survive for much longer.

Scientists are studying people in their nineties (called nonagenarians) and hundreds (called centenarians, including semi-supercentenarians of ages 105-109 years and supercentenarians, ages 110+) to determine what contributes to their long lives. They have found that long-lived individuals have little in common with one another in education, income, or profession. The similarities they do share, however, reflect their lifestyles—many are nonsmokers, are not obese, and cope well with stress. Also, most are women. Because of their healthy habits, these older adults are less likely to develop age-related chronic diseases, such as high blood pressure, heart disease, cancer, and diabetes, than their same-age peers.

The siblings and children (collectively called first-degree relatives) of long-lived individuals are more likely to remain healthy longer and to live to an older age than their peers. People with centenarian parents are less likely at age 70 to have the age-related diseases that are common among older adults. The brothers and sisters of centenarians typically have long lives, and if they develop age-related diseases (such as high blood pressure, heart disease, cancer, or type 2 diabetes), these diseases appear later than they do in the general population. Longer life spans tend to run in families, which suggests that shared genetics, lifestyle, or both play an important role in determining longevity.

The study of longevity genes is a developing science. It is estimated that about 25 percent of the variation in human life span is determined by genetics, but which genes, and how they contribute to longevity, are not well understood. A few of the common variations (called polymorphisms) associated with long life spans are found in the APOE, FOXO3, and CETP genes, but they are not found in all individuals with exceptional longevity. It is likely that variants in multiple genes, some of which are unidentified, act together to contribute to a long life.

Whole genome sequencing studies of supercentenarians have identified the same gene variants that increase disease risk in people who have average life spans. The supercentenarians, however, also have many other newly identified gene variants that possibly promote longevity. Scientists speculate that for the first seven or eight decades, lifestyle is a stronger determinant of health and life span than genetics. Eating well, not drinking too much alcohol, avoiding tobacco, and staying physically active enable some individuals to attain a healthy old age; genetics then appears to play a progressively important role in keeping individuals healthy as they age into their eighties and beyond. Many nonagenarians and centenarians are able to live independently and avoid age-related diseases until the very last years of their lives.

Some of the gene variants that contribute to a long life are involved with the basic maintenance and function of the body’s cells. These cellular functions include DNA repair, maintenance of the ends of chromosomes (regions called telomeres), and protection of cells from damage caused by unstable oxygen-containing molecules (free radicals). Other genes that are associated with blood fat (lipid) levels, inflammation, and the cardiovascular and immune systems contribute significantly to longevity because they reduce the risk of heart disease (the main cause of death in older people), stroke, and insulin resistance.

In addition to studying the very old in the United States, scientists are also studying a handful of communities in other parts of the world where people often live into their nineties and older—Okinawa (Japan), Ikaria (Greece), and Sardinia (Italy). These three regions are similar in that they are relatively isolated from the broader population in their countries, are lower income, have little industrialization, and tend to follow a traditional (non-Western) lifestyle. Unlike other populations of the very old, the centenarians on Sardinia include a significant proportion of men. Researchers are studying whether hormones, sex-specific genes, or other factors may contribute to longer lives among men as well as women on this island.

Moles are very common, especially in people with fair skin. Moles are overgrowths of skin cells called melanocytes, but the genetic factors involved in their development are not well understood. Although moles, like tumors, are an overgrowth of cells, moles are almost always noncancerous (benign). Perhaps because most moles are benign, scientists have not studied them extensively, and not much is known about their genetics. Similar numbers of moles seem to occur on individuals of different generations of a family, so a tendency to develop moles seems to be inherited, but the inheritance pattern is not well understood.

Most moles occur on parts of the body that are exposed to the sun (ultraviolet radiation), and the number of moles an individual has may increase after extended time in the sun. Moles usually begin to occur in childhood. These moles are called acquired melanocytic nevi (and include the subtype epidermal nevus). It is common for new moles to appear during times when hormone levels change, such as adolescence and pregnancy. During an individual’s lifetime, moles may change in appearance; hair may grow out of them, and they can change in size and shape, darken, fade, or disappear. Infants and the elderly tend to have the fewest moles.

Sometimes, moles are present at birth or develop during infancy. These moles, which are called congenital nevi, are almost always benign. Rarely, a very large mole, called a giant congenital melanocytic nevus, is present at birth. In rare cases, the most serious type of skin cancer (called melanoma) may develop in this type of mole.

Large, irregularly shaped and colored moles called dysplastic nevi or atypical moles can occur at any age. Although not common, they tend to be numerous, and they increase a person’s risk of melanoma. Heredity contributes to the development of dysplastic nevi and to having a higher-than-average number of benign moles. Spending a lot of time in the sun can also increase the number of moles a person has. However, moles are often found on areas of the body that are not exposed, which suggests that factors other than ultraviolet radiation from the sun, perhaps hormones or other biologic processes, are involved in triggering the development of acquired melanocytic nevi and dysplastic nevi.

Although the genetics of melanoma has been widely studied, much less is known about genes involved in the development of benign moles. Variations in several genes, including FGFR3, PIK3CA, HRAS, and BRAF, are involved with benign moles. The most-studied of these is the BRAF gene. A mutation in BRAF leads to the production of an altered protein that causes melanocytes to aggregate into moles. This altered protein also triggers the production of a tumor-suppressor protein called p15 that stops moles from growing too big. In rare cases, BRAF mutations together with deletion of the CDKN2A gene causes a lack of p15, which creates the potential for mole cells to grow uncontrollably and become cancerous (malignant). The formation of cancer is increasingly likely when combined with environmental factors, such as cell damage caused by ultraviolet radiation exposure.

In susceptible individuals (those with fair skin, light hair, skin that burns instead of tans, a family history of melanoma, and genetic risk factors such as deletion of or mutations in the CDKN2A gene), ultraviolet radiation from repeated sun exposure can damage existing moles, increasing their risk of becoming malignant. Research has shown that individuals who have an abundance of moles are at an increased risk of melanoma. However, some people who are diagnosed with melanoma have few moles, and melanoma often develops in areas of the body that are not exposed to the sun. Researchers are working to identify additional susceptibility genes to better understand the genetics of moles and their relationship with cancer.

Temperament includes behavioral traits such as sociability (outgoing or shy), emotionality (easy-going or quick to react), activity level (high or low energy), attention level (focused or easily distracted), and persistence (determined or easily discouraged). These examples represent a spectrum of common characteristics, each of which may be advantageous in certain circumstances. Temperament remains fairly consistent, particularly throughout adulthood.

Similar temperaments within a family may be attributable to shared genetics and to the environment in which an individual is raised. Studies of identical twins (who share 100 percent of their DNA) and their non-twin siblings (who share about 50 percent of their DNA) show that genetics play a large role. Identical twins typically have very similar temperaments when compared with their other siblings. Even identical twins who were raised apart from one another in separate households share such traits.

Scientists estimate that 20 to 60 percent of temperament is determined by genetics. Temperament, however, does not have a clear pattern of inheritance and there are not specific genes that confer specific temperamental traits. Instead, many (perhaps thousands) of common gene variations (polymorphisms) combine to influence individual characteristics of temperament. Other DNA modifications that do not alter DNA sequences (epigenetic changes) also likely contribute to temperament.

Large studies have identified several genes that play a role in temperament. Many of these genes are involved in communication between cells in the brain. Certain gene variations may contribute to particular traits related to temperament. For example, variants in the DRD2 and DRD4 genes have been linked to a desire to seek out new experiences, and KATNAL2 gene variants are associated with self-discipline and carefulness. Variants affecting the PCDH15 and WSCD2 genes are associated with sociability, while some MAOA gene variants may be linked to introversion, particularly in certain environments. Variants in several genes, such as SLC6A4, AGBL2, BAIAP2, CELF4, L3MBTL2, LINGO2, XKR6, ZC3H7B, OLFM4, MEF2C, and TMEM161B contribute to anxiousness or depression.

Environmental factors also play a role in temperament by influencing gene activity. In children raised in an adverse environment (such as one of child abuse and violence), genes that increase the risk of impulsive temperamental characteristics may be turned on (activated). However, a child who grows up in a positive environment (for example a safe and loving home) may have a calmer temperament, in part because a different set of genes is activated.

The likelihood of conceiving twins is a complex trait. It is probably affected by multiple genetic and environmental factors, depending on the type of twins. The two types of twins are classified as monozygotic and dizygotic.

Monozygotic (MZ) twins, also called identical twins, occur when a single egg cell is fertilized by a single sperm cell. The resulting zygote splits into two very early in development, leading to the formation of two separate embryos. MZ twins occur in 3 to 4 per 1,000 births worldwide. Research suggests that most cases of MZ twinning are not caused by genetic factors. However, a few families with a larger-than-expected number of MZ twins have been reported, which indicates that genetics may play a role. It is possible that genes involved in sticking cells together (cell adhesion) may contribute to MZ twinning, although this hypothesis has not been confirmed. Most of the time, the cause of MZ twinning is unknown.

Dizygotic (DZ) twins, also called fraternal twins, occur when two egg cells are each fertilized by a different sperm cell in the same menstrual cycle. DZ twins are about twice as common as MZ twins, and they are much more likely to run in families. Compared with the general population, women with a mother or sister who have had DZ twins are about twice as likely to have DZ twins themselves.

DZ twinning is thought to be a result of hyperovulation, which is the release of more than one egg in a single menstrual cycle. To explain how DZ twinning can run in families, researchers have looked for genetic factors that increase the chance of hyperovulation. However, studies examining the contributions of specific genes have had mixed and conflicting results. Few specific genes in humans have been definitively linked with hyperovulation or an increased probability of DZ twinning.

Other factors known to influence the chance of having DZ twins include the mother’s age, ethnic background, diet, body composition, and number of other children. Assisted reproductive technologies such as in vitro fertilization (IVF) are also associated with an increased frequency of DZ twins.