Pea plant trait genetics are relatively simple compared to what we know about genetic inheritance today. The vast majority of genetically controlled traits are not strictly dominant or recessive, so the relationship among alleles and predicting phenotype is often more complicated. For example, traits that exhibit incomplete dominance occur when a heterozygote exhibits a phenotype that is an intermediate phenotype of both alleles. In snapdragon flowers, the red flower color (R) is dominant and white is recessive (r). Therefore, the homozygous dominant RR is red and homozygous recessive rr is white. However, because the R allele is not completely dominant, the heterozygote Rr is a blend of red and white, which results in a pink flower (Figure 3.33).
An example of incomplete dominance in humans is the enzyme β-hexosaminidase A (Hex A), which is encoded by the gene HEXA. Patients with two dysfunctional HEXA alleles are unable to metabolize a specific lipid-sugar molecule (GM2 ganglioside); because of this, the molecule builds up and causes damage to nerve cells in the brain and spinal cord. This condition is known as Tay-Sachs disease, and it usually appears in infants who are three to six months old. Most children with Tay-Sachs do not live past early childhood. Individuals who are heterozygous for the functional type HEXA allele and one dysfunctional allele have reduced Hex A activity. However, the amount of enzyme activity is still sufficient, so carriers do not exhibit any neurological phenotypes and appear healthy.
Some genes and alleles can also have higher penetrance than others. Penetrance can be defined as the proportion of individuals who have a certain allele and also express an expected phenotype. If a genotype always produces an expected phenotype, then those alleles are said to be fully penetrant. However, in the case of incomplete (or reduced) penetrance, an expected phenotype may not occur even if an individual possesses the alleles that are known to control a trait or cause a disease.
A well-studied example of genetic penetrance is the cancer-related genes BRCA1 and BRCA2. Mutations in these genes can affect crucial processes such as DNA repair, which can lead to breast and ovarian cancers. Although BRCA1 and BRCA2 mutations have an autosomal dominant pattern of inheritance, it does not mean an individual will develop cancer if they inherit a pathogenic allele. Several lifestyle and environmental factors can also influence the risk for developing cancer. Regardless, if a family has a history of certain types of cancers, then it is often recommended that genetic testing be performed for individuals who are at risk. Moreover, publically available genetic testing companies are now offering health reports that include BRCA1 and BRCA2 allele testing (see the Genetic Testing section).
While Mendelian traits tend to be influenced by a single gene, the vast majority of human phenotypes are polygenic traits. The term polygenic means “many genes.” Therefore, a polygenic trait is influenced by many genes that work together to produce the phenotype. Human phenotypes such as hair color, eye color, height, and weight are examples of polygenic traits. Hair color, for example, is largely determined by the type and quantity of a pigment called melanin, which is produced by a specialized cell type within the skin called melanocytes.The quantity and ratio of melanin pigments determine black, brown, blond, and red hair colors. MC1R is a well-studied gene that encodes a protein expressed on the surface of melanocytes that is involved in the production of eumelanin pigment. Typically, people with two functional copies of MC1R have brown hair. People with reduced functioning MC1R allele copies tend to produce pheomelanin, which results in blond or red hair. However, MC1R alleles have variable penetrance, and studies are continually identifying new genes (e.g., TYR, TYRP1, SLC24A5, and KITLG) that also influence hair color. Individuals with two nonfunctioning copies of the gene TYR have a condition called oculocutaneous albinism—their melanocytes are unable to produce melanin so these individuals have white hair, light eyes, and pale skin.
In comparison to Mendelian diseases, complex diseases (e.g., Type II diabetes, coronary heart disease, Alzheimer’s, and schizophrenia) are more prevalent in humans. Complex diseases are polygenic, but their development is also influenced by physical, environmental, sociocultural, and individual lifestyle factors. Families can be more predisposed to certain diseases; however, complex diseases often do not have a clear pattern of inheritance.
Although research of complex traits and diseases continue, geneticists may not know all of the genes involved with a given complex disease. Additionally, how much genetic versus nongenetic determinants contribute to a disease phenotype can be difficult to decipher. Therefore, predicting individual medical risk and risk across different human populations is often a significant challenge. For instance, cardiovascular diseases (CVDs) continue to be one of the leading causes of death around the world. Development of CVDs has been linked to nutrient exposure during fetal development, high fat and sedentary lifestyles, drug usage, adverse socioeconomic conditions, and various genes. Human environments are diverse, and public health research including the field of Human Biology can help identify risk factors and behaviors associated with chronic diseases. Large-scale clinical genetic studies with powerful bioinformatic approaches can also help elucidate some of these complex relationships.