206
L. S. Emery and J. M. Akey
In this chapter, we discuss the prevalence of selection in the human genome and
how natural selection interacts with demographic forces to shape extant patterns of
variation. Focusing particularly on the action of positive selection, we will review
current knowledge of where and when selection has acted upon the human genome,
based on both detailed candidate gene studies and genomic scans for selection.
Additionally, we will discuss advances in models of selection and statistical methods
that are necessary for a comprehensive description of the action of selection on
the human genome. Finally, we will highlight how an understanding of selection’s
effects on variation can inform studies of human population differentiation.
9.2
Amount of Selection in the Human Genome
We will begin by discussing the amount of balancing, negative, and positive
selection that has been identified in genomic studies. Detailed descriptions of these
types of selection and how they affect genetic variation can be found in Chap. 4.
9.2.1 Balancing Selection
The two subtypes of balancing selection—overdominance and frequency-dependent
selection have been described in Chap. 4. Overdominance and frequency-dependent
selection are rare for most human traits, but both are particularly important for
immune-related genes (Charlesworth 2006). Several notable examples of overdominance have been described including the following: the cystic fibrosis F508 allele
of the CFTR gene may also prevent childhood asthma (Schroeder et al. 1995);
phenylketonuria-causing alleles of the PAH gene show molecular evidence for
overdominance, though the selective pressure is as yet unknown (Krawczak and
Zschocke 2003); and sickle cell trait alleles and thalassemia alleles at the HBB
gene provide resistance against malaria (Allison 1954; Quintana-Murci and Barreiro
2010).
The X-linked gene G6PD also shows signatures of overdominance due to
selective pressure from the Plasmodium malaria parasites. G6PD encodes the
enzyme glucose-6-phosphate dehydrogenase, which is responsible for replenishing
supplies of NADPH from NADP + . Alleles that drastically reduce the activity of
the G6PD enzyme result in oxidative damage to the red blood cells, because G6PD
is the only enzyme replacing NADPH in these cells (Verrelli et al. 2002). These
deficiency alleles are found at high frequencies in areas with a high prevalence of
malaria, including sub-Saharan Africa and the Mediterranean. Experimental studies
show that deficiency alleles in both heterozygous females and hemizygous males
reduce the risk of malaria infection by about half (Verrelli et al. 2002). The region
exhibits unusually high levels of polymorphism consistent with balancing selection.
Although this molecular signature is not completely conclusive, the confluence of
molecular, phenotypic, and population genetic data make G6PD one of the most
convincing cases of balancing selection in the human genome and one of the first to
L. S. Emery and J. M. Akey
In this chapter, we discuss the prevalence of selection in the human genome and
how natural selection interacts with demographic forces to shape extant patterns of
variation. Focusing particularly on the action of positive selection, we will review
current knowledge of where and when selection has acted upon the human genome,
based on both detailed candidate gene studies and genomic scans for selection.
Additionally, we will discuss advances in models of selection and statistical methods
that are necessary for a comprehensive description of the action of selection on
the human genome. Finally, we will highlight how an understanding of selection’s
effects on variation can inform studies of human population differentiation.
9.2
Amount of Selection in the Human Genome
We will begin by discussing the amount of balancing, negative, and positive
selection that has been identified in genomic studies. Detailed descriptions of these
types of selection and how they affect genetic variation can be found in Chap. 4.
9.2.1 Balancing Selection
The two subtypes of balancing selection—overdominance and frequency-dependent
selection have been described in Chap. 4. Overdominance and frequency-dependent
selection are rare for most human traits, but both are particularly important for
immune-related genes (Charlesworth 2006). Several notable examples of overdominance have been described including the following: the cystic fibrosis F508 allele
of the CFTR gene may also prevent childhood asthma (Schroeder et al. 1995);
phenylketonuria-causing alleles of the PAH gene show molecular evidence for
overdominance, though the selective pressure is as yet unknown (Krawczak and
Zschocke 2003); and sickle cell trait alleles and thalassemia alleles at the HBB
gene provide resistance against malaria (Allison 1954; Quintana-Murci and Barreiro
2010).
The X-linked gene G6PD also shows signatures of overdominance due to
selective pressure from the Plasmodium malaria parasites. G6PD encodes the
enzyme glucose-6-phosphate dehydrogenase, which is responsible for replenishing
supplies of NADPH from NADP + . Alleles that drastically reduce the activity of
the G6PD enzyme result in oxidative damage to the red blood cells, because G6PD
is the only enzyme replacing NADPH in these cells (Verrelli et al. 2002). These
deficiency alleles are found at high frequencies in areas with a high prevalence of
malaria, including sub-Saharan Africa and the Mediterranean. Experimental studies
show that deficiency alleles in both heterozygous females and hemizygous males
reduce the risk of malaria infection by about half (Verrelli et al. 2002). The region
exhibits unusually high levels of polymorphism consistent with balancing selection.
Although this molecular signature is not completely conclusive, the confluence of
molecular, phenotypic, and population genetic data make G6PD one of the most
convincing cases of balancing selection in the human genome and one of the first to