5

Linkage, Recombination, and Eukaryotic Gene Mapping

For many, baldness is the curse of manhood. Twenty-five percent of men begin balding by age 30, and almost half are bald to some degree by age 50. In the United States, baldness affects more than 40 million men, and hundreds of millions of dollars are spent each year on hair-loss treatment. Baldness is not just a matter of vanity: bald males are more likely to suffer from heart disease, high blood pressure, and prostate cancer.

Baldness can arise for a number of different reasons, including illness, injury, drugs, and heredity. The most common type of baldness seen in men is pattern baldness—technically known as androgenic alopecia—in which hair is lost prematurely from the front and top of the head. More than 95% of hair loss in men is pattern baldness. Although pattern baldness is also seen in women, it is usually expressed weakly as mild thinning of the hair. The trait is stimulated by male sex hormones (androgens), as evidenced by the observation that males castrated at an early age rarely become bald (though this preventive treatment for baldness is not recommended).

A strong hereditary influence on pattern baldness has long been recognized, but the exact mode of inheritance has been controversial. An early study suggested that it was autosomal dominant in males and recessive in females, which would make pattern baldness a sex-influenced trait (see Chapter 4). Other evidence and common folklore suggested that a man inherits baldness from his mother’s side of the family, exhibiting X-linked inheritance.

In 2005, geneticist Axel Hillmer and his colleagues set out to locate the gene that causes pattern baldness. They suspected that the gene might be located on the X chromosome, but they had no idea where on the X chromosome it might reside. To identify the location of the gene, they conducted a linkage analysis study, in which they looked for an association between the inheritance of pattern baldness and the inheritance of genetic variants known to be located on the X chromosome. The genetic variants used in the study were single-nucleotide polymorphisms (SNPs, pronounced “snips”), which are positions in the genome where individuals differ in a single nucleotide. The geneticists studied the inheritance of pattern baldness and SNPs in 95 families in which at least two brothers developed pattern baldness at an early age.

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Hillmer and his colleagues found that pattern baldness and SNPs from the X chromosome were not inherited independently, as predicted by Mendel’s principle of independent assortment. Instead, they tended to be inherited together, which occurs when genes are physically linked on the same chromosome and segregate together in meiosis.

As we will learn in this chapter, linkage between genes is broken down by a process called recombination, or crossing over, and the amount of recombination between genes is directly related to the distance between them. In 1911, Thomas Hunt Morgan and his student Alfred Sturtevant demonstrated in fruit flies that genes can be mapped by determining the rates of recombination between them. Using this method for families with pattern baldness, Hillmer and his colleagues demonstrated that the gene for pattern baldness is closely linked to SNPs located at position p12–22 on the X chromosome. This region includes the androgen receptor gene, which encodes a protein that binds male sex hormones. Given the clear involvement of male hormones in the development of pattern baldness, the androgen receptor gene seemed a likely candidate for causing pattern baldness. Further analysis revealed that certain alleles of the androgen receptor gene were closely associated with the inheritance of pattern baldness, and that variation in the androgen receptor gene is almost certainly responsible for many of the differences in pattern baldness seen in the families examined. Additional studies conducted in 2008 found that genes on chromosomes 3 and 20 also appear to contribute to the expression of pattern baldness.

This chapter explores the inheritance of genes located on the same chromosome. These linked genes do not strictly obey Mendel’s principle of independent assortment; rather, they tend to be inherited together. This tendency requires a new approach to understanding their inheritance and predicting the types of offspring that will be produced. A critical piece of information necessary for predicting the results of these crosses is the arrangement of the genes on the chromosomes; thus, it will be necessary to think about the relation between genes and chromosomes. A key to understanding the inheritance of linked genes is to make the conceptual connection between the genotypes in a cross and the behavior of chromosomes in meiosis.

We will begin our exploration of linkage by first comparing the inheritance of two linked genes with the inheritance of two genes that assort independently. We will then examine how recombination breaks up linked genes. This knowledge of linkage and recombination will be used for predicting the results of genetic crosses in which genes are linked and for mapping genes. Later in the chapter, we will focus on mapping with molecular markers and genome-wide association studies.