Last Updated on April 1, 2020
Genetic inheritance is a basic principle of genetics. It explains how characteristics and traits are passed from one generation to the next.
Every individual receives genetic material from both the parents. However, which gene will dominate to express itself or how the various genes interact with each other to express a certain trait or disorder forms the basis of genetic inheritance.
There are various types and modes of genetic inheritance. Each mode of inheritance results in a characteristic pattern of affected and unaffected family members.
The study of patterns of inheritance started with the work of the Austrian monk Gregor Mendel who discovered the fundamental laws of inheritance through his work on pea plants.
Types and Modes of Genetic Inheritance
There are two types of genetic inheritance
Mendelian inheritance
The traits are passed down by dominant and recessive alleles of one gene.
Non-Mendelian inheritance
The traits are not determined by dominant or recessive alleles, and they can involve more than one gene.
Mendelian Inheritance Patterns
There may be a number of alleles for a given gene. Individuals that have two copies of the same allele are said to be homozygous for that allele while individuals that have copies of different alleles are said to be heterozygous for that allele. The inheritance patterns depend on whether the allele is found on an autosomal chromosome or a sex chromosome. It also depends on whether the allele is dominant or recessive.
Autosomal Dominant Inheritance
- Only one copy of a disease allele is sufficient for an individual to express the phenotype. In other words, the disease will be expressed even if one disease allele is present and the other allele is normal (heterozygous).
- If one of the parents is affected (has one disease allele and one normal allele) and the other parent is normal ( has both normal alleles), then there is a 50% chance that their offspring will inherit the disease allele.
- Each affected individual will have at least one affected parent who carries the disease allele.
- It is also called vertical inheritance because the transmission occurs from parent to offspring.
- There is no sex predilection. Males and females are equally affected.
- Male-to-male transmission can be observed.
- Diseases that follow autosomal dominant inheritance include myotonic muscular dystrophy and Huntington disease.
Autosomal Recessive Inheritance
- Two copies of a disease allele are required for an individual to express the phenotype. In other words, the disease will be expressed only when the alleles inherited from both the parents are diseased (homozygous).
- An individual with only one copy of the disease allele (heterozygous) will not have the disease but will be able to pass the disease allele to his or her offspring. Such an individual is known as a carrier.
- The parents of an affected individual do not have the disease themselves but are carriers of the disease.
- If both the parents are carriers,
- There is a 25% chance that the offspring will inherit two copies of the disease allele (one from both parents) and will, therefore, have the disease.
- There is a 50% chance that the offspring will inherit one copy of the disease allele (from one of the parents) and will be a carrier.
- There is a 25% chance that the offspring will not inherit any disease allele and will neither have the disease nor be a carrier. Such persons will also not pass the disease to their offspring.
- There is no sex predilection. Males and females are equally affected.
- An important feature that distinguishes it from Autosomal dominant or X linked dominant inheritance is that unaffected individuals can have affected offspring.
- Autosomal recessive diseases are commonly observed in consanguineous relationships (where the couple is related by blood, eg., first cousins). This is because both the individuals have common ancestors hence, more likely to carry the same gene mutations or disease allele.
- They are also more frequently seen in certain ethnic populations because the individuals have descended from the same ancestors.
- Diseases that follow autosomal recessive inheritance include sickle cell anemia, cystic fibrosis, Wilson disease, hemochromatosis, etc.
X-Linked Dominant Inheritance
- The defective gene responsible for the disease is located on the X-chromosome. Only one copy of a disease allele on the X chromosome is required for an individual to be susceptible to an X-linked dominant disease.
- Both males and females can be affected.
- Because females have two X-chromosomes, they are more commonly affected than males. However, males can be more severely affected because they only have one copy of genes found on the X chromosome. Some X-linked dominant disorders are fatal in males.
- Unlike autosomal dominant inheritance, an affected father can’t pass the disease to his son because males inherit their X chromosome from their mothers and not their fathers.
- An affected female has a 50% chance of passing the disease allele to her offsprings.
- In the case of an affected male, the disease allele will be passed to all his daughters but none of his sons. So all the daughters but none of the sons will be affected.
- Diseases that follow X-linked dominant inheritance include hypophosphatemic rickets , oral-facial-digital syndrome type I, and Fragile X syndrome.
X-Linked Recessive Inheritance
- Similar to autosomal recessive inheritance, two copies of a disease allele on the X chromosome are required for an individual with two X chromosomes (a female) to be affected with the disease.
- Since males are hemizygous for X-linked genes (they have only one X chromosome), any male with one copy of an X-linked recessive disease allele is affected.
- Males are more frequently affected than females in a given population. This is in contrast to autosomal dominant and recessive disorders where both sexes are equally affected and X linked dominant inheritance where females are more frequently affected.
- Females will have the disease when disease alleles are present on both the X chromosomes. Females having only one affected X chromosome are carriers of the disease.
- Females affected by the disease (having 2 disease alleles) will transmit the defective gene to all their sons ( all sons will be affected) while all daughters will be unaffected carriers.
- A carrier female has a 50% chance of transmitting the disease allele to her sons and daughters.
- Affected males transmit the disease allele to all of their daughters, who are then carriers, but to none of their sons.
- Diseases that follow X-linked recessive inheritance include Duchenne muscular dystrophy, hemophilia A and hypohidrotic or anhidrotic ectodermal dysplasia.
Non-Mendelian Inheritance Patterns
Complex or Multifactorial Inheritance
- These are caused by the complex interactions between genetic factors and environmental influences.
- The genes involved can make a person susceptible to the disease, but it is the environmental factors that trigger this susceptibility.
- It is only when individuals with genetic susceptibility are exposed to certain environmental factors, that a particular trait or disease will be exhibited.
- They are very commonly observed in the population.
- Examples include heart disease, diabetes, asthma, and many birth defects, such as cleft lip and cleft palate.
- Traits such as height and weight also follow this type of inheritance. While genetic factors may predispose a person to fall within a certain height or weight range, but the ultimate height or weight will depend on a complex interplay of many other factors including nutrition, exercise, etc. Similarly, in diseases like diabetes or heart disease, genetic predisposition coupled with lifestyle and other environmental factors determine which individual will have the disease.
Mitochondrial Inheritance
- Mitochondria are present in the cytoplasm of all cells.
- Each mitochondrion contains DNA material (mitochondrial DNA or mtDNA) that is different from the one present in the chromosomes of the nucleus.
- MtDNA replicates during mitochondrial division and is passed through the female egg. A child (son or daughter) receives all its mtDNA from its mother. Hence mutations in mtDNA are inherited through the maternal line (from mother).
- These mutations can affect both males and females. However males cannot pass them further to their offsprings as the mitochondria are passed via the egg and not the sperm.
- Diseases that follow mitochondrial inheritance include Leber’s hereditary optic neuropathy, Kearns-Sayre syndrome.
Y Linked Inheritance or Holandric Inheritance
- The disease allele is present on the Y chromosome.
- An affected male passes the disease to all his sons and none of his daughters.
- These diseases never occur in females since they don’t have the Y chromosome.
- The concepts of dominant and recessive do not apply to Y-linked inheritance, as only one allele (on the single Y chromosome) is present in males.
- This is the easiest mode of inheritance to identify.
- Since the Y chromosome is small and contains very few genes, very few diseases show this type of inheritance.
- An example of a Y linked inheritance is the hairy-ear-rim phenotype seen in some Indian families or non-syndromic hearing impairment seen in a large number of males in a Chinese family.
Factors Affecting Gene Expression or Phenotype
Penetrance
Some individuals who carry the disease gene ( for example in an autosomal dominant inheritance) may not present with abnormal phenotype meaning they do not exhibit the disease. This is referred to as incomplete or reduced penetrance. The penetrance of a particular genetic change (such as a mutation) is the proportion of people with the mutation who exhibit clinical symptoms.
In neurofibromatosis type I (NF1), penetrance is approximately 80 %. This means that if 100 individuals have the disease NF1gene, only about 80 of them would have the disease.
Expressivity
It refers to the range of signs and symptoms that can be present in different people having the same genetic defect.
For example, in Marfan syndrome, in spite of the identical gene mutation some people have only mild symptoms while others have life-threatening complications affecting the heart and blood vessels.
Both reduced penetrance and incomplete expressivity have significance mainly in autosomal dominant diseases.
Age of onset of the disease
Although the genetic defect is present since birth, the disease may manifest later in life. In hereditary hemochromatosis, symptoms usually begin between 30-60 years of age.
Knowledge of the presence of a genetic defect in the family can help in the early detection of the gene mutation by genetic testing. This can help in early treatment even before the appearance of signs and symptoms.
Genetic anticipation
It is a phenomenon in which a genetic disease appears earlier with each succeeding generation. It can occur in several diseases including Huntington disease, myotonic dystrophy, etc. It occurs due to the increased number of trinucleotide repeat sequences in the DNA from one generation to the next. As a result, there is an earlier onset of disease in the younger generations accompanied by more severe symptoms.
Pleiotropy
It occurs when a mutation in a particular gene may have an effect on several traits simultaneously. This is because the gene codes for a product which is used by a number of cells or different targets that have the same signaling function. Such a gene that exhibits multiple phenotypic expressions is called a pleiotropic gene.
Phenylketonuria is an inherited disorder that affects the level of phenylalanine in the body. It is caused by a defect in a single gene on chromosome 12 that codes for enzyme phenylalanine hydroxylase. The genetic defect affects several systems, including the nervous system and the skin.
Mutational heterogeneity
It is defined as mutations at two or more genetic loci that produce similar phenotypes or disease.
Mutations in ten different genes ave been associated with a heritable increased risk of breast cancer and other cancer syndromes. These include mutations in BRCA1 BRCA2, p53, PTEN CHECK2, ATM, NBS1, RAD50, BRIP1, and PALB2 genes.
Read more about BRCA Gene Mutation and Testing
Genomic imprinting
Two copies of genes (one each from the mother and father) are inherited in each person. Usually, both copies of each gene are active, or “turned on”. However, in certain cases, only one copy is normally turned on.
For certain genes, only the copy inherited from the father is active. While for others, only the maternal copy is active. This phenomenon is known as genomic imprinting. Maternal imprinting means that the allele of a particular gene inherited from the mother is silent and the paternally- inherited allele is active. The reverse is true for paternal imprinting.
Normally, even if the copy of the gene inherited from one parent is defective, the second normal copy from the other parent is present. However, in the case of imprinting, even though two copies of the gene are present, the normal one may be inactive. In other words, there is no substitute active allele, due to which imprinted genes are more vulnerable to the negative effects of mutations. Also, genes that are otherwise recessive can be expressed if the dominant gene is imprinted and hence inactive.
Human diseases involving genomic imprinting include Angelman syndrome, Prader–Willi syndrome and male infertility.
Uniparental disomy
It occurs when a person receives two copies of a chromosome from one parent and no copy from the other parent. It can occur randomly during the formation of egg or sperm or may occur during early fetal development.
Usually, this phenomenon does not produce any ill-effect on health or development. Since most genes are not imprinted, it is immaterial whether a person inherits both copies from one parent or one copy from each parent.
In some cases with genomic imprinting, however, it becomes significant. A person may receive both copies of a gene from one parent but due to genomic imprinting, those genes are inactive. Such a person will lack any active copies of essential genes which can lead to delayed development, intellectual disability, etc.
Examples include Prader-Willi syndrome (deletion on chromosome 15 in the paternal chromosome), Angelman syndrome (deletion on chromosome 15 in the maternal chromosome), Beckwith-Wiedemann syndrome, etc.
Significance of Genetic Inheritance
Counseling for disease prevention
Genetic inheritance helps to understand the pattern followed by disease in transmission to future generations. This can be used to counsel the parents about the possibility of the disease in their offsprings so as to prevent it. It can thus reduce the burden of genetic diseases in society.
Early diagnosis and treatment
Genetic inheritance patterns can help in the early diagnosis and treatment of disease prevalent in the family.
Disease prevention
Lifestyle modifications and a healthy diet play a significant role in preventing multi-factorial inheritance disorders like diabetes, heart disease, etc.
Gene therapy
Disorders following Mendelian inheritance are potential candidates for gene therapy.
Investigation of evolutionary lineages
Mitochondrial DNA inheritance is used to investigate evolutionary lineages, both recent and remote. Y-chromosome DNA polymorphisms can be used to follow the male lineage in large families or through ancient ancestral lineages. It can also be used in species identification in ecology studies.
References
- Bates GP (2005) History of genetic disease: the molecular genetics of Huntington disease — a history. Nat Rev Genet 6:766–773
- Badano JL, Katsanis N (2002) Beyond Mendel: an evolving view of human genetic disease transmission. Nat Rev Genet 3:779–789
- Beaudet AL, Perciaccante RG, Cutting GR (1991) Homozygous nonsense mutation causing cystic fibrosis with uniparental disomy. Am J Hum Genet 48:1213
- Bell J (1934) Huntington’s chorea. Treasury of human inheritance 4. Galton Laboratory
