Pedigree analysis
Pedigree analysis is a method used to trace the inheritance of traits and genetic diseases through family trees over multiple generations. By constructing a graphical representation, known as a pedigree chart, individuals can visualize the relationships among family members and identify who carries specific traits. In these charts, males are represented by squares and females by circles, with shading indicating whether an individual is affected by a trait. This analysis helps genetic counselors assess the risk of inherited diseases and assists researchers in understanding how traits are passed down within families.
There are four primary modes of inheritance detectable through pedigree analysis: autosomal dominant, autosomal recessive, X-linked dominant, and X-linked recessive. Each mode has distinct patterns regarding how traits are expressed in males and females, particularly with X-linked traits, which often demonstrate different inheritance patterns due to the presence of only one X chromosome in males. Pedigree analysis also faces challenges, such as the complexities introduced by adoption and assisted reproductive technologies, as well as the variable expression of traits. Modern applications have expanded with advancements in genetic testing and gene mapping, allowing for more accurate identification of inherited conditions. Despite its limitations, pedigree analysis remains a crucial tool in genetic counseling and research.
Pedigree analysis
SIGNIFICANCE: Charts called pedigrees are used to represent the members of a family and to indicate which individuals have particular inherited traits. A pedigree is built of shapes connected by lines to indicate relationships. Pedigrees are used by genetic counselors to help families determine the risk of genetic disease and by research scientists to study how particular traits are inherited.
Overview and Definition
Pedigree analysis involves the construction of family trees that can be used to trace inheritance of a trait over several generations. It is a graphical representation of the appearance of a particular trait or disease in related individuals, along with the nature of the relationships.
Standardized symbols are used in pedigree charts. Male individuals are designated by squares, and female individuals by circles. The symbols representing individuals affected by a trait are shaded, while those for unaffected individuals are not. Heterozygous carriers are indicated by shading of half of the symbol, and carriers of X-linked recessive traits have a dot in the middle of the symbol. Matings are indicated by horizontal lines linking the mated individuals. Offspring of the mated individuals are linked to their parents by a vertical line intersecting with the horizontal mating line.
The classic way to determine the mode of inheritance of a trait in animals is to conduct experimental matings of large numbers of individuals. Such experimental matings between humans are neither ethical nor feasible, so it is necessary to infer the mode of inheritance of traits in humans through the use of pedigrees. Large families with good historical records are the easiest to analyze. Once a pedigree is established, it can be used to determine the likely mode of inheritance of a particular trait and, if the mode of inheritance can be determined with certainty, to determine the risk of the trait appearing in offspring.
Typical Pedigrees
There are four common modes of inheritance that can be detected using pedigree analysis: autosomal dominant, autosomal recessive, X-linked dominant, and X-linked recessive. Autosomal traits are governed by genes found on one of the autosomes (chromosomes 1–22), while the genes that cause X-linked traits are found on the X chromosome. Males and females are equally likely to be affected by autosomal traits, whereas X-linked traits are never passed on from father to son but can be passed from father to daughter, and all affected males in a family received the mutant allele from their mothers.
The pattern of autosomal dominant inheritance is perhaps the easiest type of Mendelian inheritance to recognize in a pedigree. A trait that appears in successive generations and is found only among offspring when at least one of the parents is affected is normally due to a dominant allele.
If neither parent has the characteristic phenotype displayed by the child, the trait is recessive. For recessive traits, on average, the recurrence risk to the unborn sibling of an affected individual is one in four. The majority of X-linked traits are recessive. The hallmark of X-linked recessive inheritance is that males are much more likely to be affected than females, because males are hemizygous—that is, they possess only one X chromosome, while females have two X chromosomes. Therefore, a recessive trait on the X chromosome will be expressed in all males who possess that X chromosome, while females with one affected X chromosome will be asymptomatic carriers unless their other X chromosome also carries the recessive trait.
X-linked dominant traits are rare but distinctive. If a male is affected and a female is unaffected, all the pair's daughters will be affected, and none of their sons will be. If the female is affected and the male is not, their risk of having an affected child is one in two, regardless of the sex of the child. In the general population, females are more likely to be affected than males, but males are usually more severely affected, and the trait may be lethal in males.
Usefulness
Pedigrees are important both for helping families identify the risk of transmitting an inherited disease and as starting points for researchers in identifying the genes responsible for inherited diseases. Mendelian ratios do not apply in individual human families because of the small size. Pooling of families is possible.
However, even using large, carefully constructed records, pedigrees can be difficult to construct and interpret for several reasons. Tracing family relationships can be complicated by adoption, children born out of wedlock, and assisted reproductive technologies that result in children who may not be genetically related to their parents. Additionally, people are sometimes hesitant to supply information because they are embarrassed by genetic conditions.
Many traits do not follow clear-cut Mendelian ratios. There are numerous extensions and exceptions to Mendel’s laws that can confound efforts to develop a useful pedigree. In diseases with variable expressivity, some of the symptoms of the disease are always expressed but may range from very mild to severe. In autosomal dominant diseases with incomplete penetrance, some individuals who possess the dominant allele may not express the disease phenotype at all. Some traits have a high recurrent mutation rate. An example is achondroplasia, in which 85 percent of cases are due to new mutations in offspring whose parents both have normal phenotypes. Traits due to multifactorial inheritance have variable expression as a result of the involved genes' interactions with the environment. Early-acting lethal alleles can lead to embryonic death and a resulting dearth of expected affected individuals. Pleiotropy, which refers to a situation in which a single gene controls several functions and therefore has several effects, can result in different symptoms in different affected individuals. Finally, one trait can have a different basis of inheritance in different families. For example, mutations in any one of more than four hundred different genes can result in hereditary deafness.
Modern Applications
Genetic counseling is one of the key areas in which pedigrees are employed. A genetic counseling session usually begins with the counselor taking a family history and sketching a pedigree with paper and pencil, followed by use of a computer program to create an accurate pedigree. The Human Genome Project has greatly increased the number of genetic disorders that can be detected by heterozygote and prenatal screening. A large part of the genetic counselor’s job is to determine which, if any, specific genetic tests are appropriate for whom.
Although genetic tests for many disorders are now available, the genes involved in many others have yet to be identified. Therefore, most human gene mapping utilizes molecular DNA markers, which reflect variation at noncoding regions of the DNA near the affected gene, rather than biochemical, morphological, or behavioral traits. A DNA marker is a piece of DNA of known size, representing a specific locus, that comes in identifiable variations. These allelic variations segregate according to Mendel’s laws, which means it is possible to follow their transmission as one would any gene’s transmission. If a particular allelic variant of the DNA marker is found in individuals with a particular phenotype, the DNA marker can be used to develop a pedigree. The DNA from all available family members is examined, and the pedigree is constructed using the presence of the DNA marker rather than phenotypic categories. This method is particularly useful for late-onset diseases such as Huntington’s disease, as affected individuals may not know they carry the deleterious allele until they are in their forties or fifties, well past reproductive years. Although using DNA markers is a powerful method, crossover in the chromosome between the marker and the gene can cause an individual to be normal but still have the marker that suggests presence of the mutant allele. Thus, for all genetic tests there is a small percentage of false positive and false negative results, which must be factored into the advice given during genetic counseling. Researchers in 2024 were hopeful that artificial intelligence (AI) could one day be used to efficiently create and analyze pedigrees.
Key Terms
- allelesalternate forms of a gene locus, some of which may cause disease
- autosomal traita trait that typically appears just as frequently in either sex because an autosomal chromosome, rather than a sex chromosome, carries the gene
- dominant allelean allele that is expressed even when only one copy (instead of two) is present
- hemizygousmale humans are considered to be hemizygous for X-linked traits, because they have only one copy of X-linked genes
- heterozygous carriersindividuals who have one copy of a particular recessive allele that is expressed only when present in two copies
- homozygotean organism that has identical alleles at the same locus
- recessive allelean allele that is expressed only when there are two copies present
- X-linked traita trait caused by a gene carried on the X chromosome, which has different patterns of inheritance in females and males because females have two X chromosomes while males have only one
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