Genetics and inheritance

DEFINITION: The passage of traits from parents to offspring in discrete units called genes.

The Rules of Inheritance

The primary genes of interest to heredity consist of a set of coded directions for making proteins. Each gene codes for a protein; distinct versions of a gene, which encode slightly different versions of the protein, may be carried in the same or different individuals. The distinct versions of a gene, called alleles, are responsible for differences in hereditary traits among individuals. Each individual receives a combination of alleles encoding proteins that directly or indirectly determine traits, such as eye, skin, and hair color; height; and, to a degree, characteristics of personality, behavior, and intelligence.

In molecular terms, genes consist of a sequence of chemical units called nucleotides, linked end to end in long, linear deoxyribonucleic acid (DNA) molecules. There are four kinds of nucleotides in DNA, and each gene has its own nucleotide sequence. The alleles of a gene differ slightly in nucleotide sequence—some alleles differ in the substitution of only a single nucleotide. There are many thousands of genes arranged in tandem on the DNA molecules of a human cell. Each DNA molecule is known as a chromosome. In humans, the chromosomes occur in twenty-three pairs, for a total of forty-six chromosomes. The two members of a chromosome pair contain the same genes in the same order, but different alleles of a gene may be present in the two members of a pair. One member of a chromosome pair is derived from the female parent of the individual. The other member is derived from the male parent. These are called the maternal and paternal chromosomes of the pair.

Inheritance and the variation in traits among individuals depend on two processes that separate and rejoin the chromosome pairs in sexual reproduction. One is a division mechanism, meiosis, which occurs in cell lines, leading to egg or sperm cells. Meiosis separates the chromosome pairs and places one member of each pair in an egg or sperm cell. The particular combination of maternal and paternal chromosomes delivered to an egg or sperm cell is random. This random segregation, as it is called, is one source of the variability among offspring in a family. Because there are so many chromosomes, the possibility that two egg or sperm cells produced by the same individual could receive the same combination of maternal and paternal chromosomes is very small—equivalent to one chance in 8.4 million. Another important source of variability comes from a mechanism that occurs before the pairs are separated in meiosis. In this mechanism, called recombination, the two members of a chromosome pair line up side by side and exchange segments perfectly and reciprocally. As a result, alleles are exchanged between the pairs, generating new combinations of alleles. The variability generated by recombination adds to that produced by independent segregation of maternal and paternal chromosomes, so that it is essentially impossible for an individual to produce two egg or sperm cells that are genetically the same.

The second process underlying inheritance is fertilization, in which a sperm and an egg cell fuse, rejoining the twenty-three pairs of chromosomes. Fertilization is another random process, in which any of the millions of sperm cells ejaculated by a male and any of the hundreds of egg cells carried in a female may join. The total variability generated by independent segregation of alleles, recombination, and random union of gametes is such that each human individual, except identical twins, receives a unique combination of alleles. Thus, the possibility that any individual has or will ever have a genetic double in the human population, except for an identical twin, is essentially zero. (In the case of identical twins, a single fertilized egg divides to produce two separate, genetically identical cells; instead of remaining together to produce a two-celled embryo, as is normally the case, the cells separate to create two embryos, which develop into genetically identical individuals.)

Because chromosomes occur in pairs, each individual receives two alleles of every gene of the human complement. The two alleles may be the same or different. Some alleles are dominant in their effects, so that one copy of the allele on either chromosome is sufficient to produce the trait encoded in the allele. Other alleles are recessive, so that both chromosomes of the pair must carry the allele for the trait to appear in offspring. In humans, few physical traits are determined by Mendelian inheritance, meaning controlled by a single gene with two alleles. Mendelian inheritance patterns have been identified in blood type, albinism, sickle cell anemia, and cystic fibrosis. Most traits are the result of polygenic genetic factors, which involve complex interactions between several genes; environmental influences can also play a role in polygenic traits, called multifactorial inheritance.

Some traits do follow certain inheritance patterns, but there are exceptions. For example, brown eyes tend to be dominant over blue eyes. If either chromosome carries the brown eye allele, the individual will usually have brown eyes. To have blue eyes, an individual usually carries two genes for blue eyes. Human traits that tend toward dominant inheritance include nearsightedness and farsightedness, astigmatism, dark or curly hair, early balding in males, typical body pigment (as compared to albinism), supernumerary fingers or toes, short fingers or toes, and webbing between fingers and toes. Alleles that tend to be expressed in a recessive fashion include blond hair, straight hair, and congenital hearing loss.

Although each individual normally carries a maximum of two alleles of any gene, several or many alleles of a gene may exist in the human population as a whole. The major histocompatibility complex (MHC), for example, occurs in hundreds of different alleles throughout the human population—so many that unrelated individuals are unlikely to carry the same combination of MHC alleles. The proteins encoded in these alleles are recognized by the immune system as “self” or “foreign.” Unless the same, or a very similar, combination of MHC alleles is present, cells are recognized by the immune system as foreign, and the cells are destroyed. Therefore, MHC combinations recognized as foreign are the primary factor in the rejection of tissue or organ transplants among humans. If the transplant does not come from an individual with the same or a very similar MHC combination, rejection is likely unless the immune system is suppressed by drugs, such as cyclosporine. The best donor for a transplant is a close relative, who is most likely to have a similar MHC combination. Because identical twins have the same MHC combination, tissues and organs can be transplanted between them with no danger of rejection.

In most humans, sex is determined by a pair of chromosomes, either XX or XY. Females have two members of the pair, the X chromosomes, which have the same genes in the same order but which may have different alleles of the genes. One member of the XX pair was derived from the female’s father, and the other from her mother. Males have only one member of this pair, a single X. In addition, males have a small, single chromosome, the Y, which is not present in females. Thus, females are XX, and males are XY. During meiosis in females, the XX pair is separated, allowing an egg cell to receive either member of the pair. In males, the X and Y are separated, so that a sperm cell receives either an X or a Y. In fertilization, the X chromosome carried by the egg may be joined with an X-carrying sperm, producing a female (XX), or the egg may be fertilized by a sperm cell carrying a Y, producing a male (XY). Thus, in humans, the sex of the offspring is determined by the type of sperm cell, an X or a Y, that fertilizes the egg. Most genes carried on an X chromosome have no counterparts on the Y chromosome. Therefore, traits encoded in genes on the X chromosomes (almost none are carried on the Y) are inherited differently from traits carried on other chromosomes of the set, in a pattern known as sex-linked inheritance.

In rare cases, chromosome variations such as XXY (Klinefelter syndrome), X0 (Turner Syndrome), XYY (Jacob's Syndrome), or another chromosomal configuration can occur.

Disorders and Diseases

Many human diseases, involving every system in the body, depend on the presence of particular dominant or recessive alleles and are directly inherited. Only the disposition for development of other diseases is inherited—that is, some individuals inherit a combination of alleles that increases the possibility that a genetically based disease will develop during their lifetimes.

The list of diseases contracted through inheritance of a dominant allele is long and impressive. Among the more important of these diseases are achondroplasia, in which individuals are short statured; familial hypercholesterolemia, in which cholesterol concentration in the blood is abnormally high, leading to vascular disease, particularly of the coronary arteries; Huntington’s disease, a disease characterized by dementia, delusion, paranoia, and abnormal movements that begins in persons between twenty and fifty years of age and progresses steadily to death in about fifteen years. Marfan syndrome, a disease of connective tissues involving the skeleton, eyes, and cardiovascular system, characterized by elongated limbs, abnormal position of the eye lens, and structural weakness of blood vessels, particularly of the aorta; neurofibromatosis, characterized by tumors dispersed throughout the body and coffee-colored skin lesions (café-au-lait spots); polycystic kidney disease, in which dilated cysts grow in the kidneys and interfere with kidney function, leading to hypertension and chronic renal failure; spherocytosis, another disease in which blood cells are fragile and easily broken during travel through the circulatory system, producing anemia and jaundice; and thalassemia, a group of diseases most common in persons of Mediterranean descent in which hemoglobin production is faulty, leading to anemias that range from mild to severe.

Diseases caused by recessive genes also appear in the human population. Although many individuals are carriers of these diseases, affected individuals are rare because both alleles must be present in the recessive form for the disease to develop. Diseases in this category include albinism; sickle cell disease, common in persons of African descent, in which hemoglobin is faulty, leading to fragility of red blood cells, anemia, blockage of blood vessels, and susceptibility to infection; phenylketonuria (PKU), in which the amino acid phenylalanine accumulates in excess in the bloodstream, leading to nervous system damage including intellectual disability; Tay-Sachs disease, most common in persons of Ashkenazi Jewish ancestry, characterized by accumulation of lipid molecules in nerve cells leading to motor incoordination, blindness, and mental deterioration; and glycogen storage diseases, with symptoms ranging from cramps to serious muscular and cardiac disease and convulsions. Sickle cell disease is recessively inherited. A person with one copy of the sickle cell gene makes sufficient normal hemoglobin that symptoms of the disease occur only under extremely low oxygen conditions. Cystic fibrosis, one of the most common of genetically determined diseases in people of European ancestry, is probably also attributable to a recessive allele. In this disease, sweat and mucus-secreting glands are affected; the most serious effects are caused by the secretion of unusually thick and viscid mucus, leading to blockage of ducts in the lungs, liver, pancreas, and salivary glands. Most critical to survival is blockage of passages in the lungs, producing a chronic cough and persistent pulmonary infections. The average life expectancy of persons with cystic fibrosis in the 2020s was around fifty years, compared to just thirty years in the 1990s. The Cystic Fibrosis Foundation predicted that the median age of survival for patients born between 2020 and 2024 would be sixty-five.

Several diseases are caused by recessive genes carried on the X chromosome and are inherited in sex-linked patterns. Among these are hemophilia, in which the blood-clotting mechanism is deficient, raising the risk of uncontrolled bleeding; red-green color blindness; fragile X syndrome; Hunter syndrome; and Duchenne muscular dystrophy, characterized by progressive muscular weakness. Duchenne muscular dystrophy appears early in life, progresses rapidly, and leads to death in most cases by the age of thirty or forty.

Because males receive only one copy of the X chromosome, recessive genes are fully expressed in males—there is no chance for a normal allele to compensate for the effects of the recessive gene. For a sex-linked disease to appear in females, both X chromosomes must carry the recessive allele. For these reasons, sex-linked recessive diseases are much more common in males than in females; for some, the appearance of the disease is limited almost exclusively to males.

The molecular basis for some genetically based diseases is known. In familial hypercholesterolemia, for example, receptors for cholesterol on cell surfaces are faulty or not produced, preventing the normal uptake of cholesterol from the bloodstream. As a result, cholesterol accumulates and reaches a dangerously high concentration in the blood. In persons carrying dominant alleles for familial hypercholesterolemia on both chromosomes of the pair, coronary arterial disease advances so rapidly that death from a heart attack by the age of twenty is frequent. The disease is among the most common of genetically based defects—about one in five hundred persons has at least one allele for hypercholesterolemia and develops premature coronary artery disease. In PKU, individuals lack an enzyme normally produced in the liver. The enzyme phenylalanine hydroxylase converts excess phenylalanine into the amino acid tyrosine. Without the enzyme, phenylalanine taken in the diet accumulates to dangerously high levels in the body. Some forms of PKU are treatable by restricting dietary intake of phenylalanine from infancy onward.

Some people have a genetically determined predisposition to develop certain cancers with greater frequency than the average in the population. Between 5 to 10 percent of cancers are strongly predisposed—that is, individuals inherit a marked tendency to develop the cancer. Among these are familial retinoblastoma, in which retinal tumors develop; familial adenomatous polyps of the colon; and multiple endocrine neoplasia, in which tumors develop in the thyroid, adrenal medulla, and parathyroid glands. Often underlying these strongly predisposed cancers is the inheritance of a faulty gene (called an oncogene) that promotes uncontrolled cell division, or the opposite—inheritance of a faulty gene that, in its normal form, suppresses cell division (called a tumor suppressor gene). Typically, oncogenes are inherited as dominant genes, while tumor suppressor genes are inherited as recessive genes. In addition, some cancers, including breast, ovarian, and colon cancers, other than familial adenomatous polyps, show a degree of predisposition in family lines.

Perspective and Prospects

The primary features of meiosis and fertilization, random segregation of chromosome pairs in meiosis and random rejoining of pairs in fertilization, make heredity subject to analysis by mathematical techniques. In fact, mathematical analysis of heredity was carried out successfully before there was any understanding of meiosis or DNA. The groundwork for this analysis was laid down in the 1860s by an Austrian monk, Gregor Mendel. Mendel’s research approach and his conclusions were so advanced that they were misunderstood and unappreciated during his lifetime.

Mendel chose garden peas for his research because they could be easily grown and possessed several hereditary traits that were known to breed true—that is, to appear consistently in offspring. Mendel crossed pea plants with different traits in various combinations. On analyzing the results of his crosses, Mendel realized that the number of offspring exhibiting different traits could be explained mathematically if he assumed that parents contain a pair of factors governing the inheritance of each trait. Furthermore, he concluded that the factors separate, or segregate, independently as gametes are formed and are reunited randomly at fertilization. He also discovered that some traits are inherited as dominant and some as recessive. Mendel’s factors were later called genes.

Until Mendel’s time, inheritance was commonly believed to occur through a blending of maternal and paternal characteristics. Mendel’s work showed instead that traits are passed on as units; depending on whether a trait is dominant or recessive, it may appear in all offspring or only in a definite, predictable percentage. Some time after Mendel’s discoveries, in the early twentieth century, meiosis was discovered. At this time, Walter Sutton pointed out that Mendel’s genes and chromosomes behave similarly in meiosis and fertilization: Both genes and chromosomes occur in pairs that separate randomly in meiosis and are rejoined at fertilization. Genes were, therefore, concluded to be carried on the chromosomes. Further genetic research confirmed that Mendel’s findings with plant genes also apply to animals, including humans, and worked out many additional features of inheritance, including genetic recombination and sex linkage. In the 1950s, almost one hundred years after Mendel’s findings, James D. Watson and Francis Crick discovered the structure of DNA and deduced that hereditary information is encoded in the sequence of nucleotides in DNA.

Research in human genetics differs from genetic investigation in other organisms because, for obvious reasons, it is impossible to set up experimental crosses to test whether particular diseases are inherited. Instead, human family lines are analyzed carefully in pedigrees to trace the appearance of disease over several generations. If a disease is genetically determined, it presents in definite patterns as dominant, recessive, or sex-linked among parents and offspring in the pedigrees. On this basis, prospective parents can be counseled on the chances that their offspring will develop a hereditary disease.

In June 2000, Francis Collins, director of the National Human Genome Research Institute, and J. Craig Venter, of Celera Genomics, announced that they had jointly sequenced the entire human genome and that the first working draft was available. In 2003, researchers with the Human Genome Project reported that they had identified close to 25,000 genes in human DNA and sequenced the 3 billion chemical base pairs of which it is made up. Sequencing the human genome allowed scientists to directly compare healthy DNA to DNA harboring disease genes. By 2013, researchers had discovered the genetic basis for nearly 5,000 diseases and developed genetic tests for nearly 2,000 conditions or diseases. Additionally, genetic testing became faster and less expensive as sequencing technology became more sophisticated. Although these advances led to a greater understanding of certain disease processes, as well as the development of some diagnostic procedures, potential therapy, and cures, scientists cautioned that the human genome is larger and more complex than initially thought. More research remained necessary before treatments could be developed to target illnesses, such as those caused by several gene variants.

By the mid-2020s, the online catalog of human genes and genetic disorders called the Online Mendelian Inheritance in Man (OMIM) listed over 6,000 genetic diseases and the genes associated with these conditions. Experts worldwide continued to identify new genetic variants and genetic conditions during this time. In February 2024, the National Institutes of Health’s research program, All of Us, reported the identification of over 275 million genetic variants that were previously unknown. In 2025, a study used a revolutionary analytical approach to identify sixty-nine previously unknown genetic determinants of rare diseases, thirty of which were the subject of existing experimental evidence. Some of these included genes and their proposed associated conditions included monogenic diabetes (UNC13A), epilepsy (RBFOX3), schizophrenia (GPR17), and Charcot–Marie–Tooth disease (ARPC3). However, as many as 80 percent of patients with rare diseases remained undiagnosed after genomic sequencing in the mid-2020s.

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