April 14, 2008 (Revised 9-18-08)
James L. Breeling
Alopecia Areata-Genes Plus Other Factors
Androgenetic Alopecia: One Gene Down, More to Go
Why does hair grow on one's scalp and body? Why does a person lose scalp hair? The answer to the first question is: It's in one's genes. The formation of hair follicles and the growth of hair is genetically prefigured.
The answer to the second question is: Genes are involved, but the genes are not all known and there are other reasons for hair loss that may or may not involve genes. The answer is still being worked out.
Genes from Embryo to Infancy
Genes involved in the formation of hair follicles are present from the fertilization of an egg by sperm, and their influence can be seen early in the development of an embryo (see Hair Science: How and Why Hair Grows). These genes have a long evolutionary history (see Hair Science on the Cutting Edge). Their long history is testimony to nature's conservatism: a gene that serves a useful purpose is likely to be conserved and used over and over again, even across orders and species.
A prime example is the wingless genes first identified in Drosophila melanogaster, the fruit flies that are a staple in genetic research, and subsequently found in mammals and humans. Their descriptor shortened to Wnt when they occur in mammals and humans, the wingless genes are essential for synthesis of the cascade of signaling molecules that prompt the formation of hair follicles. The Wnt proteins synthesized by Wnt genes (gene names are always italicized, their protein products written in Roman script) influence stem cells to differentiate into hair follicle tissue.
Another example is the DNA sequence called the Homeobox, first found in the fruit fly and subsequently identified as an essential group of genes involved in the development of embryologic patterning in mammals and humans.
For more description and discussion of Wnt genes, see http://ghr.nlm.nih.gov/geneFamily=wnt,
Genes from Infancy to Adulthood
After the hair follicle is formed in the embryo, it continues to acquire the signaling pathways it will need to produce, maintain and cycle hair for its lifetime. Production of hair requires synthesis of the proteins (keratins) and other molecules from which a hair is constructed, patterned (straight, wavy, curly, frizzy) and pigmented (blond, red, brown, black). (see Hair Science: How and Why Hair Grows).
Although a number of hair abnormalities are recognized, very little is known regarding their ultimate cause and/or their genetic transmission (inheritability). Some congenital hair abnormalities are associated with congenital physical and mental developmental anomalies that have been mapped onto specific chromosomes.
Study of some relatively rare conditions has opened windows into understanding how variations in genes may bring about hair abnormalities.
An example is investigation of a rare genetic disorder called atrichia or alopecia universalis which results in almost complete absence or inactivity of hair follicles over the entire body. It is an autosomal recessive disorder (see Genetic Pedigree Patterns) studied mainly in affected Pakistani families. Investigators found that the condition is caused by mutations in the human version of the Hairless gene first identified in mice. A mouse version of atrichia universalis has been recognized. Work of the investigators of this condition can be found in the paper "Alopecia universalis associated with a mutation in the human hairless gene", published in the journal Science 1998; 279:720-724.
While the condition is rare, study of atrichia universalis has provided important understanding of genetic mutation and transmission in hair follicle pathology.
Genetic Pedigree Patterns
Straight-forward inheritance patterns (pedigrees) are called Mendelian, named for Gregor Mendel who first recognized inheritance patterns in the 19th Century. Not all inheritance patterns are Mendelian; there are many variations on Mendelian patterns.
Important Mendelian patterns in humans are:
Also important in human pathologic conditions is the inheritance pattern called X-linked recessive. These conditions occur in males but the gene for the condition is transmitted by carrier females who carry one gene for the specific condition. An affected male cannot transmit the disorder genetically to his sons, but all of his daughters will be carriers of the gene.
There is More Than One Genetic Code
When we refer to "the genetic code" we usually mean the organization and orchestration of the 25,000 to 30,000 human genes identified by the Human Genome Project. This definition omits overlying orchestration of genes by other "codes" that regulate or alter the expression of genes.
Discovered more than 50 years ago, but studied seriously only within the past decade, is an epigenetic code that orchestrates the expression of genes without altering their DNA sequence. One of the most dramatic illustrations of the influence of the epigenetic code is seen in identical twins who share identical DNA sequences in their genes-but, one twin becomes seriously ill with a genetically predisposed disease such as Type 1 diabetes or cancer and the other twin does not. Something has happened to dysregulate the gene expression in the ill twin and no mutated gene has been identified. The dysregulation is explainable by epigenetics. How does the epigenetic code function to alter the products of genes without causing DNA mutation? Increasingly, epigenetics is seen to be interaction of genes with the external environment or with the internal environment of an individual's body. External environmental influences may be toxic substances such as industrial chemicals, smokes and gases, viruses or other pathogens, and ingested toxins. Internal environmental influences may include entities such as the body's immune response system.
Some investigators believe that the phenomenon called epigenetics developed as an evolutionary response to protect genes from being mutagenically altered by environmental influences. Epigenetic alteration of genetic DNA can occur in two ways:
1. DNA is chemically altered by a process called methylation, which alters the processes by which gene expression is turned "on" or "off".
2. Alterations are made in the structures called histones, which are the core bodies around which chromosomal DNA is wrapped. Each histone has a "tail" to which more than 20 chemical tags can attach; some of these tags can change the way in which genetic information is expressed.
Some of the epigenetic changes in gene expression are believed to be inheritable.
SNPs and Haplotypes
When we say a person has "normal" anatomic or physiologic characteristics, we are reciting a long-standing belief that is increasingly shown to be faulty if not incorrect. At the level of our genes, "normal" is a slippery term.
The reason: the human genome consists of 25,000 to 30,000 genes, but these genes contain about 10 million variants (mutations) called single nucleotide polymorphisms (SNPs, pronounced "snips"). There are millions of these SNP variances that occur in different combinations, so that no two human beings can ever be completely alike-even identical twins. The SNPs have accumulated over a long evolutionary history, and they are still being accumulated today. This, in addition to the differences accounted for by various combinations and orchestrations of up to 30,000 genes, can be reflected in varying patterns of anatomy, physiology, health and disease.
What Is a Single Nucleotide Polymorphism (SNP)?
What Is a Haplotype?
A single nucleotide polymorphism (SNP) is a variation in a single nucleotide (DNA building block). While SNPs may occur in apparent random order, they are often not independent of one another. A SNP is frequently associated with specific SNPs on the same chromosome. When SNPs cluster or associate they form a "haplotype".
Because specific SNPs may often be found strongly associated with one another in a haplotype, the finding of one SNP at one site can predict the presence of other specific SNPs on the same chromosome. The clustering or haplotype can have implications for variations in a person's anatomy, physiology, or predisposition to pathologic conditions.
Following completion of the first phase of the Human Genome Project that identified the majority of genes in the human genome, investigators launched the International HapMap Project. The purpose of the HapMap Project was to describe and map the common patterns of human genetic variations (haplotypes) associated with health and disease. The HapMap Project has been very successful in meeting its goals. HapMap Project data-a haplotype map of the human genome-are available to all investigators to use in studies of genetic variation (see http://www.hapmap.org).
Investigations of the inheritance patterns of conditions causing hair loss suggest that specific haplotypes may sometimes be involved in inheritance patterns that are not classically Mendelian.
An example of HapMap utility: recent studies of genetic variation targeting predisposition to lung cancer suggest that SNPs on specific genes on chromosome 15 are associated with increased risk for lung cancer in both smokers and non-smokers.
MicroRNAs: the Newest Frontier in Gene Regulation
Scientific research is exciting for many reasons, and one outstanding reason is discovering something that was previously unsuspected. A recent example is recognition of the role played by microRNAs in regulating genes. Ribonucleic acid (RNA) is the "other" complex nucleic acid-in addition to deoxyribonucleic acid (DNA)-involved in gene expression. Over the past several decades scientists have been characterizing various forms of RNA and their role in gene regulation and expression. Only very recently it was discovered that cells use very short RNA molecules dubbed microRNAs to regulate gene expression. Roles for microRNAs have been indicated in pathogenesis of several diseases including cancer, diabetes and heart failure. The possibility that microRNAs could become therapeutically useful has attracted venture capitalists into new microRNA start-up companies.
Alopecia Areata: Genes Plus Other Factors
A discussion of alopecia areata requires consideration of the influence of genes as well as the possibility of genes being influenced by environment (Epigenetics).
Alopecia areata is a hair-loss condition that affects up to 6 million Americans. It is not related to androgenetic alopecia, the most common cause of pattern hair loss in both men and women. A defining feature of alopecia areata is patchy hair loss on the scalp that can progress to loss of hair over the entire scalp or even the entire body; hair loss may or may not be permanent (see http://www.alopeciaareatainfo.com).
Apparent associations have been noted between the presence of alopecia areata in a person, and the presence of other conditions with a genetic basis including psoriasis, thyroid disease, autoimmune polyglandular syndrome type 1, and Down's syndrome-conditions that have autoimmune and/or inflammatory characteristics. The simultaneous occurrence of alopecia areata with another condition prompted investigators to look for "candidate genes"-that is, genes that might occur in close proximity on the same chromosome. More recently, advances in technology allowed use of broad genome screening to look for mutational variants that could be associated with a specific condition (see http://www.nature.com/jidsp/journal/v8/n2/full/5640117a.html).
Investigations have indicated that genes on at least four chromosomes may be involved in alopecia areata, as well as (1) epigenetic factors such as interaction between hair follicle genes and the body's immune system, and (2) environmental influences unspecified to date.
Other Hair Loss Conditions
Genetic components have been difficult to differentiate from other causes in many hair loss conditions:
Androgenetic Alopecia: One Gene Down, More to Go
Androgenetic alopecia is the most common cause of hair loss in men, and occurs in women as well. In men it is called male-pattern hair loss, and the patterns of male balding have been well characterized (see http://www.ishrs.org and see About Your Hair Loss). Androgenetic alopecia patterns of hair loss are significantly different in women than in men and the underlying cause(s) may be more complex than in men.
A genetic predisposition for androgenetic alopecia has long been recognized. The condition quite obviously "runs in the family". What has not been known is (1) what genes are involved, (2) if there is one or more than one genetic pedigree pattern, and (3) why genetic transmission is not straight-forward Mendelian (Genetic Pedigree Patterns).
The Role of Androgens, the Androgen Receptor and the X Chromosome
While the underlying cause of androgenetic alopecia is genetic, the direct cause is the way the hair follicle interacts with the hormone dihydrotestosterone (DHT) and its receptor. The parent molecule of DHT is testosterone-an androgenic or "male" hormone that is essential to the development of male characteristics (testosterone is also present in females, but at much lower levels than in males).
Testosterone is converted to the physiologically more active DHT by the action of an enzyme, 5-alpha-reductase Type 2. This gene has two subtypes, Types 1 and 2; Type 2 is believed to be more influential in androgenetic alopecia. The gene that synthesizes this enzyme is known to be located on chromosome 2. The gene for 5-alpha-reductase Type 1 is located on chromosome 5. DHT has a variety of important functions throughout the body. When mutation in the 5-alpha-reductase Type 2 gene renders the enzyme unable to convert testosterone into DHT, the result is 5-alpha-reductase Type 2 deficiency and associated anomalies in male sexual development.
In order to be effective, DHT must pass unhindered into its target cells. After entering the cell, DHT "docks" with an androgen receptor (AR). The AR is a specially configured protein that binds to the DHT molecule. The configuration of the receptor protein is determined by the AR gene that synthesizes the protein. When the docking is effective, the DHA-receptor complex binds to DNA in the nucleus of the cell and regulates the activity of DHT-responsive genes. The DHT-AR complex has specific affinity for the DNA in target cells, initiating the regulation of gene expression that effects hair growth.
A SNP mutation in the AR gene can change the configuration of the androgen receptor and thus the manner in which the DHT-receptor complex interacts with a gene. For example:
The AR gene is the only gene that has been convincingly shown to be associated with androgenetic alopecia. Specific SNPs in the AR gene have been shown to be "markers" for predisposition to androgenetic alopecia that begins early in a man's life. Not known is whether these AR gene variations are a primary cause of androgenetic alopecia, or one among other gene variations. Since the AR gene is located on the X chromosome, it is inherited from the mother, indicating that certain variations in androgenetic alopecia follow a female line of inheritance. However, this association does not explain paternal influences on androgenetic alopecia.
The X Chromosome Role in Androgenetic Alopecia
Chromosomes are sticky, string-like biologic entities that carry our genes. Every cell of one's body carries a full complement of 23 pairs of chromosomes inherited from mother and father. Twenty-two pairs of the chromosomes are autosomal-not unique to a person's gender. One pair is sex-linked: the female X chromosome and the male Y chromosome. A biologic human female carries two X chromosomes (one of which is largely silenced as to genetic activity, perhaps because one X chromosome is all she needs). A biologic human male carries one X chromosome inherited from his mother and one Y chromosome inherited from his father.
The Y chromosome is the smallest of the 23, but it carries some of the genes that confer "maleness". The X chromosome, on the other hand, carries many genes, some with functions still not entirely understood. In fact, the "X" description given this chromosome was originally assigned because the "X" stood for "unknown function".
Although the DNA sequence of the X chromosome has now been determined, mysteries remain-for example, why is one of the two copies of the X chromosome in a biologic female silenced, and why are there so many repeat elements in sequences between the X chromosome's genes (56% repeats in the X chromosome versus 45% average in autosomal chromosomes)? The answer may be found eventually in understanding the evolution of sex chromosomes in mammals.
Sequencing of the DNA of the X chromosome has substantially advanced understanding of how the chromosome functions. A total of 1,098 genes are identified on the X chromosome. Some of these genes were found to be evolutionarily conserved across mammalian and other species-that is, a gene that "worked" well in fruit flies or mice was retained and put to use in humans.
A total of 153,146 SNPs were mapped onto the genes of the X chromosome, of which 901 were identified as candidates for influencing coding functions (see SNPs and Haplotypes). Of the 1,098 genes identified on the X chromosome, 99 were found to encode proteins expressed in male sex organs and various types of tissue. Previous investigations have shown the X chromosome to be associated with a disproportionately high number of inherited diseases; of these, 168 have been associated with SNPs in 113 X chromosome genes.
It is SNPs on the androgen receptor (AR) gene of the X chromosome that have been identified as markers for predisposition to early-onset androgenetic alopecia.
While evidence for involvement of the AR gene in androgenetic alopecia is persuasive, there is evidence to suggest that SNPs in the AR gene are not the whole story regarding androgenetic alopecia:
No investigator has suggested that current lines of research will lead to prevention of androgenetic alopecia.