Vol. 18 No 2 | Winter 2016
Genetics: an introduction
Dr Katie Ellis
Genetic Counsellor (FHGSA)

This article is 8 years old and may no longer reflect current clinical practice.

Although Johann Gregor Mendel (1822–1884) is considered the father of modern genetics, observations on the inheritance of physical traits in humans can be found as early as 300CE. The Charaka Samhita, commonly held to be a foundational text for Ayurvedic medicine, says a child’s characteristics are determined by four major factors:

  1. the characteristics from the mother’s reproductive material;
  2. the characteristics from the father’s reproductive material;
  3. the diet of the pregnant mother; and
  4. the soul that enters the fetus.

Although point four is more controversial in today’s world, together these observations are rather remarkable, even including the effects of the mother’s diet. Further observations on the inheritance of physical traits in humans date back to ancient Greek literature.

Back to Mendel, the first to describe the fundamentals of inheritance, his epic pea plant experiments on 10 000 pea plants over eight years gave us Mendel’s Laws of Inheritance. Mendel studied the inherited traits in the pea plants (such as colour and shape) over generations and found traits are inherited from parents in set patterns. His First Law (the Law of Segregation) states that each inherited trait is defined by a gene pair. The offspring inherits one allele from each parent when the sex cells unite in fertilisation.

The Second Law (the Law of Independent Assortment) states that genes for different traits are sorted separately from one another so that the inheritance of one trait is not dependent on the inheritance of another. Finally, the Law of Dominance states that an organism with alternative forms of a gene will express the form that is dominant.

Sadly for Mendel, his extensive and meticulous work went largely unnoticed or misunderstood until the 1900s. There are a number of critical contributors to the history of genetics, but there isn’t the space in this article to highlight them all. Numerous individuals expanded on the work of previous contributors to describe and prove the basis of heredity as we now know it.
I will outline a few of the key players.

Essential contributions in the 1860s were made by Walter Flemming, who discovered chromosomes (although that term wasn’t used until later). He recognised that chromosomal movement during mitosis offered a mechanism for the distribution of nuclear material during cell division. In 1969, Friedrich Miescher, a Swiss biochemist, was the first to isolate DNA inside the nuclei of human white blood cells. He named it ‘nuclein’, but later changed it to ‘nucleic acid’ and, finally, deoxyribonucleic acid (DNA).

Phoebus Levine, a Russian biochemist, made several breakthroughs in 1919. He was the first to discover the order of the three major components on a single nucleotide (phosphate-sugar-base), the first to discover the carbohydrate component of RNA (ribose), the first to discover the carbohydrate component of DNA (deoxyribose) and the first to correctly identify the way RNA and DNA molecules are put together.

In 1944, Oswald Avery (among others) reported that DNA was the substance that transferred genetic material. Erwin Chargaff, another biochemist, was able to draw two major conclusions in 1950:

  • that nucleotide composition of DNA varies among species; and
  • the total number of purines (adenine and guanine) in a DNA molecule is always equal to the total number of pyrimidines (thymine and cytosine) – this is known as Chargaff’s Rule.

Chargaff’s Rule and Rosalind Franklin’s work on x-ray diffraction studies of DNA, which provided images of the helical structure of DNA fibres in 1951, were pivotal in helping James Watson and Francis Crick to determine the molecular structure of DNA in 1953.

From that point in history, the developments in our understanding of human genetics have been rapid and numerous. Most publicised, perhaps, is the Human Genome Project that told us that we have approximately 30 000 genes on our chromosomes (far fewer than we suspected) and that mutations in our DNA are very common. Some mutations have an effect on an individual, whereas others seem to be inconsequential. Understanding variations in the genome and their affects gave rise to genomics and this seems to be where the future of genetics is heading. Let us turn for a moment to where all this work fits into practice.

Patterns of inheritance

Following Mendel’s work, we have the general patterns or rules of inheritance. Of course, we need to remember that sometimes rules are made to be broken. The work above means we now know that humans carry 46 chromosomes in 23 pairs (one of each from our mother, one of each from our father). Of these 23 pairs, the first 22 pairs are the same regardless of sex and the 23rd pair determines the sex. Two X chromosomes make a female, an XY makes a male. In essence, having a Y chromosome makes one male and the lack of a Y results in a female. The first 22 pairs are known as ‘autosomes’ and the final pair as ‘sex chromosomes’.

Autosomal dominant inheritance

Autosomal dominant (AD) inheritance means that the gene is carried on one of the autosomes, so affects males and females in equal proportion, and means that an alteration of one gene is sufficient to cause disease. Although the diagnosis is the same in family members with AD conditions, the disease can be very variable within families. Some individuals may have a mild form of disease, whereas others can be severely affected. Even siblings can vary in their presentation. This can make counselling rather complex for practitioners and families, particularly with prenatal diagnosis, as predictions of disease severity can be difficult.

Some clues that the patient’s family may have an AD disease are: there are approximately equal proportions of males and females affected, each generation has affected individuals, and all forms of transmission through the generations are seen (male-male, male-female, female-female, female-male). Some examples of AD disease often encountered in practice include Marfan syndrome, myotonic dystrophy, BRCA 1 breast cancer and Von Willebrand disorder.

Autosomal recessive inheritance

Autosomal recessive (AR) inheritance means an individual needs to carry two mutated copies of the gene to exhibit the disease. We all carry a number of recessive mutations that remain hidden in the family. Most carriers of recessive conditions have no symptoms of the condition and, importantly, no family history, as the disease is only revealed when the carrier meets another carrier. Generally speaking, AR conditions are often severe in nature and present similarly within a family. In each pregnancy, the chance of having a child affected with the disease if both parents are carriers is 25 per cent. There is a 50 per cent chance (with each pregnancy) of producing a carrier, and a 25 per cent chance of having an unaffected child (who is also not a carrier).

Common AR conditions include cystic fibrosis (CF), congenital adrenal hyperplasia (CAH) and phenylketonuria (PKU). Interestingly, given medical advances, it is now not unusual to encounter a pregnant woman who is affected with CF (or CAH or PKU) herself. Obviously, the chance of her offspring being affected with any of these disorders is dependent on her partner’s carrier status. However, each of her offspring will be carriers, regardless of sex.

Sex-linked conditions

Sex-linked conditions, as the name suggests, are carried by either the X or Y chromosome. X-linked conditions have been given more press and attention over the years, owing to the sheer number of genes, and therefore disorders, linked to the X chromosome. Traditionally, we’ve talked of conditions where the mother is the carrier and her male children exhibit symptoms of the disease. Female carriers of an X-linked condition have a 50 per cent chance of their male children being affected with the disease. Female offspring will have a 50 per cent chance of being carriers of the condition.

It is not unusual for a carrier of an X-linked condition to have some symptoms of the condition itself over time. Carriers of haemophilia, for instance, can also have altered clotting factors. However, the symptoms are generally far less severe than in affected males. The reason for this phenomenon is X-inactivation.

X-inactivation is a process whereby one of the female’s X chromosomes is switched off. Generally this is a random process in each cell, so either the paternal or maternal X is silenced. Skewed X-inactivation can also occur, whereby a disproportionate amount of either the maternal or paternal X chromosome is silenced. If the functionally normal gene is switched off in higher proportions or in cells reliant on the function of that gene, symptoms of the diseased gene will appear. Common X-linked conditions include haemophilia and Duchenne muscular dystrophy.

An interesting X-linked disease is Fragile X syndrome. Fragile X syndrome is the most common form of inherited intellectual impairment. The FMR-1 gene is composed of a triplet repeat sequence (CGG) that, when expanded to a critical level, impairs production of a protein vital for brain development. Fragile X was the first time we saw that healthy males could in fact pass on the condition to their daughters (who are all carriers). Previously, the assumption was that if a male was asymptomatic for a condition, he was unaffected and therefore would not pass the condition on. The condition then follows the general rules of X-linked inheritance in that the carrier daughters have a 25 per cent chance of having an affected son in each pregnancy and a 25 per cent chance of having a carrier (or affected) daughter in each pregnancy. Importantly, female pre-mutation carriers of Fragile X syndrome have a 20 per cent chance of premature ovarian failure before the age of 40.

Both X-linked recessive and X-linked dominant conditions exist. In very general terms, female carriers of X-linked recessive conditions are less likely to exhibit symptoms (although these include muscular dystrophy and Fragile X syndrome). X-linked dominant inheritance is very rare, with Rett syndrome being one example.

Further study on the Y chromosome and its relationship with disease came to the fore during the new millennium. Micro-Y deletions can cause lowered fertility or infertility in the male. Intracytoplasmic sperm injection (ICSI) can be performed as part of an IVF cycle to allow the individual to have biological children. It should be noted that all his male children will also have the deletion and subsequent infertility.

Other modes of inheritance

There are other modes of inheritance, not originally described by Mendel, but nonetheless very important.

Chromosomal inheritance

Approximately 1:500 individuals carry a balanced translocation in their chromosomes. This means that although they have all the genetic material and the standard number of chromosomes, they don’t carry the information in the standard way. In those carrying a balanced reciprocal translocation, a piece of one chromosome has broken off and swapped positions with another piece from another chromosome. For the individual, problems tend to only arise when they attempt to have children. The implications depend on how large the translocated pieces are, but in practice the carrier may have issues with fertility or recurrent pregnancy loss, as the fetus inherits an unbalanced rearrangement (either too much genetic information or not enough). In some cases, offspring are born with a number of medical issues, including major malformations and mental impairment, owing to the unbalanced material.

Carriers of Robertsonian translocations have 45 chromosomes, but actually have the full complement of genetic material. Robertsonian translocations occur when there is a fusion at the centromere of two acrocentric chromosomes. In humans, it is seen most commonly involving chromosomes 13, 14, 15, 21 and 22. Other forms do not lead to a viable outcome. Robertsonian translocation carriers are also at increased risk of infertility, miscarriage and children with unbalanced chromosomes.

Mitochondrial inheritance

While most of our genes are contained on the chromosomes inside the nucleus of the cell, some genes are located in the mitochondria of the cell. The mitochondria and the DNA inside it are passed on through the mother’s eggs. In simple terms, the role of mitochondria in the cell is to produce energy for the cell and therefore the rest of the body. The amount of mitochondria in each cell is variable.

A mitochondrial mutation can result in biochemical problems, owing to the absence or impairment of enzymes involved in the respiratory chain. This leads to a reduction in the supply of the energy source adenosine triphosphate (ATP) that drives various reactions essential for function and growth.

Generally mitochondrial disorders are progressive and often crippling, involving many body systems. Counselling is complex, owing to the diversity of disease and variability within families, due to the variable mitochondrial load in each cell.

What else, what next?

In addition to the basic inheritance patterns, we cannot forget the interaction between genes and environment. There are a number of conditions that are due to multifactorial inheritance and there are likely to be many more reported as we enter the age of genomics. We know that some mutations confer a susceptibility to a disease and that other factors can modify that risk further. One dramatic example of this is the reduction in neural tube defects with an increase in folate consumption.

Epigenetics occurs when there are heritable changes to the gene expression, without causing a change in the DNA itself. Epigenetic changes alter the way a gene is switched on or off. Genetic imprinting and X-inactivation are the best examples of epigenetics and disease, instances of these types of disease include Prader-Willi syndrome and Angelman syndrome.

Looking to the future, genomics is now moving to the fore with the advent of whole genome sequencing (WGS) and whole exome sequencing (WES). These advances are likely to bring both exciting and daunting changes to genetics and medicine. While a patient’s entire genome can be sequenced relatively easily, we are yet to understand all the variations that are found. Variants of unknown significance will be revealed as will unexpected findings. The complexity of understanding and explaining that information could be difficult, but not insurmountable!

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