Modern Practices

In fact, various means of influencing what genotypes future children will possess have been widely practised in many countries for the last several decades. In contrast to early 20th century eugenics, the aim of the modern practices is not to effect changes at the population level, but to enable individuals to control their reproduction. Thus, individuals, and not governments, decide which actions to take, from those that are technically and legally available. Crucially, an individual must always have an option to do nothing. This paradigm is sometimes called liberal or libertarian eugenics, although, due to negative connotations of the word eugenics, this term is not used widely.

Instead, the process of evaluating probable outcomes of reproductive decisions, and of conveying the conclusions to individuals who contemplate these decisions, may be called reproductive counseling (or simply counseling, for brevity). It can occur before or after conception, and can utilize data on both genotypes and phenotypes. Currently, data on complete genotypes are not routinely used for counseling and, instead, only one or several genes are investigated. This practice is known as genetic screening. Preconception counseling can be either “premarital", offered before the potential parents have any children, or “family", offered to parents that already have at least one child. Currently, no government mandates any actions based on the results of any form of counseling, at least legally.

Deliberate choice of partners for reproduction is an important adaptation for having more numerous and fit offspring. It is ubiquitous within the animal kingdom and, of course, humans are no exception. However, natural mate choice is based only on phenotypes. The rationale for premarital counseling is that phenotypes can be misleading, if deleterious alleles remain phenotypically cryptic. Thus, data on the genotypes of would-be parents may help to predict phenotypes of their future children.

The simplest and the most practically important situation of this kind appears when both parents are healthy heterozygous carriers of pathological recessive alleles of the same autosomal gene, because their child will have a 25% chance of being either a homozygote, if these alleles are identical, or a compound heterozygote, if they are different (Figure 2.3 and Figure 2.17). Either way, the child will have the corresponding Mendelian disease, at least in the case of fully penetrant loss-of-function alleles. Similarly, if a woman is a heterozygous carrier of a pathological recessive allele of an X-chromosome gene, 50% of her sons will have this allele on their only X chromosome and, thus, will be affected, regardless of the genotype of the father.

Current guidelines recommend “pan-ethnic” premarital screening of all people in the USA for only two particularly common autosomal recessive diseases, cystic fibrosis and spinal muscular atrophy, for which the overall frequencies of carriers are 1/30 and 1/80, respectively. However, in some populations recessive deleterious alleles of one or several autosomal genes are anomalously common, apparently because they offer, when heterozygous, some protection against a locally prevalent disease (see Chapter 10). Salient examples are alleles which, when homozygous, cause sickle-cell anemia (several African and South Asian populations, in some of which the frequency of carriers is 1/7), thalassemia (a number of Mediterranean and Middle Eastern populations; e.g., in the Republic of Cyprus the frequency of carriers is 1/7), and Tay-Sachs and several other diseases (e.g., Ashkenazi Jews, in which the frequency of Tay-Sachs disease carriers is 1/25). In such populations, screening of prospective parents for the locally common disease-causing alleles can make a big difference. In several countries premarital counseling that involves genetic screening for such alleles is a condition of legal marriage. Still, a prospective couple can marry regardless of the outcome of this screening.

Genetically, the choice of a sperm donor is analogous to the choice of a mate. However, each donor can potentially become a biological father of over 100 children. Also, rejecting a particular anonymous donor is not involved with any emotional cost, unlike a decision to cancel a planned marriage. Thus, genetic screening of potential donors makes a lot of sense. Nevertheless, there is no consistent approach to this issue. In particular, the USA does not mandate any screening, and cryobanks that provide donor sperm follow rather different practices. Some of them screen all donors only for disease- causing alleles of cystic fibrosis and spinal muscular atrophy genes, and others screen for alleles that can cause over 20 recessive Mendelian diseases.

Family counseling is particularly important if something is seriously wrong with at least one of the children that the couple already has, because this increases the odds of the same disease in their future children. The first, crucial step is to establish the diagnosis for the sick child. If a child of any sex has an autosomal recessive Mendelian disease, any future child has a risk of 25%, and if a boy has an X-linked recessive disease, only future boys are at 50% risk. In the case of a dominant disease, inherited from one of the parents but not manifested in her or him due to incomplete penetrance, the risk is equal to half the penetrance of the pathological allele.

Until recently, it was thought that if a child has a Mendelian disease due to a de novo mutation that occurred in one of the parents (see Chapter 13), the risk of the same disease for future children is not elevated, because the mutant allele should be absent in other gametes produced by the same parent. Now we know that this is not true, because the de novo mutation that caused the disease is often a part of a cluster (see Chapter 4), especially if inherited from the mother. Empirically, the risk for other children can be as high as several percent.

If a child of the couple has a genetically complex disease, the risk for future children also has to be established empirically. For example, siblings of a child with autistic spectrum disorder (ASD) have 6-8% chance of also having this condition. In this case, the risk is higher if the affected child is a girl, apparently because it takes a larger complement of ASD-causing alleles to produce symptoms in a girl than in a boy.

A principal limitation of preconception counseling is that the genotype of the would- be child is still unknown, so that all predictions regarding their phenotype must be based on Mendel laws and, thus, can only be probabilistic. Postconception counseling is free from this limitation. The genotype of a would-be child may be investigated either in the course of reproduction by in vitro fertilization (IVF) before an embryo is implanted (“preimplantation diagnosis”) or during pregnancy (“prenatal diagnosis”). Usually, several embryos are produced in preparation for IVF, and preimplantation diagnosis may help to determine which of them will be implanted. Prenatal diagnosis may lead to abortion of the affected fetus or, rarely, to in utero therapy. Recently, non-invasive prenatal diagnosis, based on fetal DNA that is normally present in the maternal blood, became possible starting from the 10th week of pregnancy. Prenatal diagnosis by means of ultrasound imaging can also detect serious anomalies of the fetal phenotype.

In most industrialized countries, testing fetal phenotypes is advised for all pregnancies. In contrast, current guidelines do not recommend any genetic screening of embryos or fetuses, unless their risk of having a Mendelian disease is known to be elevated. If a mother is older than 35 years, this substantially increases the risk of a de novo aneuploidy. In all other cases, de novo mutations are individually too rare to justify genetic screening of all fetuses at the current level of knowledge (see Chapter 15). Thus, this screening is performed only if genotypes of the parents imply a high risk due to transmission of pre-existing pathological alleles, for example, if both of them are known to be heterozygous carriers of the same autosomal recessive disease.

If preconception counseling established a high disease risk, the would-be parents generally have the following options: (i) take chances and do nothing; (ii) do not have children together; or (iii) use postconception counseling. The second option can take many forms. The bride and groom can call off a planned marriage, or marry but refrain from having biological children and, perhaps, adopt, or marry and procreate by using donor sperm for in utero insemination (IUI) or donor eggs for IVF. However, by far the most commonly used option is the third one. Because IVF is expensive and invasive, postconception counseling usually relies on prenatal diagnosis.

For example, in the Republic of Cyprus, although its population overwhelmingly belongs to the Eastern Orthodox Church which generally opposes abortion, nearcomplete eradication of thalassemia was achieved almost entirely by genetic screening of fetuses and abortion of those affected. Universal premarital screening plays only a secondary role, alerting carrier couples (about 1 in 50) to the 25% risk. The same is true for eradication of Tay-Sachs disease among secular Jews in Israel.

Even in traditionalist Saudi Arabia, where marriages are arranged and abortion of affected fetuses is illegal, only a fraction of marriages are called off after premarital counseling establishes that the prospective spouses are both carriers of thalassemia. Apparently, only in several Ultra-Orthodox Jewish communities premarital counseling alone was almost 100% effective in eradicating Tay-Sachs and several other autosomal recessive diseases common among Ashkenazi Jews, because almost all at-risk marriages are called off.

Abortion due to genetic diseases or phenotypical anomalies of the fetus is legal in almost all industrialized countries with a few exceptions, such as Ireland. For example, in France ~0.5% of pregnancies are now aborted for these reasons, which led to a drastic reduction of birth frequencies of a number of severe conditions. Even in the case of Down's syndrome, 80% of affected fetuses are aborted there, despite this condition being not as grave as many other genetic diseases.

Although the aim of reproductive counseling is wellness of individuals, it, nevertheless, affects the gene pool of the population. When carriers of an autosomal recessive disease abstain from marrying each other and choose other partners, this leads to an increase in the frequency of the disease-causing allele, relative to what would happen if they intermarry and produce sick children who would not reproduce. In contrast, if a woman who carries an X-linked recessive allele abstains from reproduction, this purges this allele from the gene pool. However, such effects are small and apparently do not guide individual reproductive decisions.

All the practices described above are passive, in the sense that they do not involve deliberate changes of germline genotypes (germline genotype modification, GGM). So far, there is only one GGM technique that can be applied to humans, being approved in Great Britain in 2015. This technique exploits the fact that eukaryotic mitochondria have their own genotypes (see Chapter 1). When these genotypes carry a disease- causing mutation, it can be replaced, together with mitochondria, by donor mitochondria with normal genotypes. One way of doing this is to transfer the maternal nuclear genotype (“spindle”) from the mother's egg into the donor egg with healthy mitochondria in its cytoplasm, whose own spindle was removed, and to fertilize the resulting egg with the father's sperm, in preparation for IVF (Figure 14.1). Then, the child develops from a zygote in which only the nucleus belongs to their parents, and 16 569 nucleotides

Replacement of the nuclear genotype of the donor egg with that from the mother's egg

Figure 14.1 Replacement of the nuclear genotype of the donor egg with that from the mother's egg.

of their genotype, out of 3.2 billion, come from the woman who donated her egg (in mammals, the sperm does not transmit mitochondria). This complicated procedure would be unnecessary if the pathological allele (usually, just one wrong nucleotide) could be reverted to its normal state in the genotypes of the maternal mitochondria; however, this is currently impossible (see Chapter 15).

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