The genes of living beings are the functional units of inheritance on which the physical and physiological characteristics that make up the organism depend. The Human Genome Project made it possible to sequence, i.e., read from end to end, the DNA nucleotide bases of our chromosomes. We have known the structure — and to a large extent the function — of human genes since 2003, when the Human Genome Project was completed. Our genome contains about 3.175 billion nucleotide base pairs, the building blocks of the DNA molecule,   which encode around 21,000 genes. These are responsible for the synthesis of proteins, which in turn are components of the structural and functional framework of cells. It also contains another series of non-coding regions. In reality, only ~1.5% of the DNA of the human genome is involved in genetic information specific to genes or related to them, and therefore in the traits specific to each individual.

It should be noted that there may be several variants or mutations of each gene, so-called “alleles”. Each individual has two alleles in his or her genome, one from each parent. As a result, there is an enormous diversity of allelic combinations and, therefore, of variation between individuals in human populations. Some allelic variants of our genes are responsible for physiological or morphological alterations and, accordingly, for hereditary diseases.

Having said this, it should be remembered that, in our genome, as in the rest of the higher species, there are two types of genes. First are the so-called “major genes”, which determine the simple or Mendelian qualitative traits. Each individual has two alleles for each gene (one maternal and one paternal), whose combination is unequivocally manifested with respect to the trait they determine. Second are the “minor genes” or “polygenes.” These are systems of multiple genes distributed throughout the genome that influence the same quantitative trait. They determine the so-called complex traits because they add up their effects on the manifestation of the character under the influence of the environment to varying degrees.

Preimplantation Genetic Diagnosis (PGD)

More than twenty years after the completion of the Human Genome Project, one of its applications is the development of diagnostic methods to detect the presence of alleles related to hereditary diseases in the DNA of a person’s cell samples. These analyses can be performed at any time in a person’s biological cycle, in the embryonic, foetal or adult phase, since the genetic information constituted at the time of fertilization remains unchanged in the organism throughout life.

PGD is performed on a cell sample from embryos originating from in vitro fertilization (IVF) techniques, either conventional or intracytoplasmic injection (ICSI). The analysis requires the application of an invasive method, which consists of taking a biopsy of one or two cells in the early stages of embryo development, in the morula stage, when they have between 4 and 16 cells. After the analysis has been performed on the DNA of these cells, the selected embryos are transferred to the uterus when the blastocyst stage is reached. Preimplantation Genetic Diagnosis is mainly used to avoid the implantation of embryos carrying altered genes.

It should be noted that there are a number of technical limitations. The first of these is in regard to the predictive value of the findings resulting from the analysis of the allelic combination of the genes analyzed, since the genetic information detected may not be determinant for the disorders or diseases. There is a possibility that the embryos in whose DNA some abnormality is discovered will not develop that particular condition in the future. This is because the detection of a structural modification does not provide information about the degree of “expressivity” or severity that the corresponding disease would reach, which is very dependent on epistatic factors and interactions with other genes. The problem of a failure to correlate structure and function (or if preferred, genotype and phenotype) adds a degree of uncertainty to embryo selection. Moreover, the analysis of one or two cells does not allow scientists to rule out “false positives” or “false negatives” due to “mosaicism” (some of the cells of the embryo in the morula stage could contain genetic variants due to mutations).

Preimplantation Genetic Diagnosis is effective for the detection of more than a hundred hereditary diseases due to simple or monogenic Mendelian systems, such as most of those that produce inborn errors of metabolism or others that are easy to detect by PCR (polymerase chain reaction), such as spinal muscular atrophy, cystic fibrosis, haemophilia, Huntington’s disease, monogenic breast cancer (BRCA1 and BRCA2 genes), achondroplasia, neurofibromatosis, etc.

While the capacity of PGD is real for most so-called Mendelian systems, which are determined by a single gene, it is not equally applicable to cases of complex diseases determined by polygenic systems, in which multiple minor genes are involved that add up their effects. Examples of these types of diseases are cardiovascular diseases, adult-onset diabetes, asthma, obesity, cancer, etc. The characteristic of these systems is that it is not only polygenes that are involved in the effects, but also the environment, both the internal physiological one, as well as epigenetic or other external factors. In these types of traits, environmental factors overlap with the genes themselves to a greater or lesser extent, making it difficult to estimate the degree of “expressivity” of the trait, as it depends on the genes and the environment.

Nevertheless, progress has been made in this type of analysis in recent years thanks to the emergence of next-generation DNA sequencers and the new technology of “massive sequencing”, which allows the genetic profile of individual DNA samples to be determined in less time and at a much lower cost than a few years ago. Despite the immense size of the human genome, only about 2% (about 48 million base pairs) are part of the so-called “exons”. These are the regions of the genes that actually code for proteins, so the goal for diagnostic purposes is to implement techniques to study this part of the genome. Massive sequencing is already applied in Preimplantation Genetic Diagnosis in embryos and prenatal care during pregnancy, and even in paediatrics, in children who have not yet developed a genetic disease. Today there are several American paediatric hospitals that are developing exome sequencing for newborn children, such as BabySeq, which is performed at Boston Children’s Hospital in collaboration with other institutions.

Massive sequencing allows us to study the part of the human genome involved in many simple and complex traits determined by Mendelian or polygenic systems, which expands the repertoire of conventional Preimplantation Genetic Diagnosis applications. For polygenic systems in which an environmental influence is added to the effects of genes, it is still very difficult to make predictions about phenotypic effects, which is what the prediction of polygenic risk described below applies to.

Bioethical aspects of PGD polygenic risk prediction

Even acknowledging that Preimplantation Genetic Diagnosis is an objective advance from a biotechnological point of view, there is no room for a positive consideration from a bioethical perspective, since embryos are human lives and its application entails the selection and discarding of these human lives in their early stage of development. It should be remembered that embryonic and foetal development is a continuous process from the fusion of the pronuclei of the sperm and egg until birth, and it is still the same person until death. From this perspective, when an embryo is selected or eliminated, a human life is selected or eliminated at its early stage of development.

Therefore, Preimplantation Genetic Diagnosis, which is carried out in order to select one among a usually high number of embryos produced by IVF according to a desired genetic profile, is a paradigm of “liberal eugenics”.

Recently, the Opinion Group of the Bioethics and Law Observatory at the University of Barcelona issued a report coordinated by Drs. Gemma Marfany, Professor of Genetics, and Itziar de Lecuona, Director of the Bioethics and Law Observatory – UNESCO Chair of Bioethics at the University, in which they analyse the bioethical implications of embryo selection by calculating the so-called “polygenic risk”, based on information from massive sequencing DNA analysis, which allows access to the most important part of the human genome.

In this report, the use of new sequencing technologies in the DNA of embryos is examined in the light of Bioethics and the “polygenic risk” is evaluated. i.e., estimation of the risk that the DNA of the embryo being analysed is potentially carrying unwanted complex traits, determined by polygenic systems involved in complex diseases. The report criticizes the value of these calculations, which actually offer a confusing probabilistic risk estimate, although it is intended to equate them with the certainty of Mendelian systems involved in monogenic diseases. Among other reasons, in the vast majority of characteristics based on polygenic systems, few differences in polygenic risk are to be expected for embryos derived from the same couple, so according to the report, the selection is not supported by a robust scientific argument.

The report rightly describes the use of this methodology as “liberal eugenics”, not only for the prediction of negative characteristics, but for the detection in embryos of genetic factors that determine future desirable cognitive or intellectual abilities, or physical or behavioural characteristics. This is an increasingly common practice, given the availability of techniques and the tendency of society to use them for personal satisfaction or improvement in well-being.

The problem is that there is not enough information or knowledge about what and how many genes are involved in complex characteristics, determined by polygenic systems, whose degree of combined phenotypic manifestation is variable and dependent on environmental factors. Trying to relate the variations in DNA observed for a quantitative trait that lacks references to the correct sequences is an insubstantial claim. Worse still is basing the calculations on fictitious references built on algorithms that use data from DNA biobanks of primarily white European populations. The biases of these types of references invalidate the reliability of the calculations. Thinking that genes decide everything, especially in polygenic characters, is a very naive reductionism.

Many of our actions as humans, especially those that concern behaviour — kindness, aggressiveness, abusive instinct, depressive nature, sexual orientation, etc. — are not inherited, but acquired. Others, such as intellectual capacity, oral ability, the ability to perform a musical or artistic activity, etc. are the result of effort, education and the personal will to acquire them. It is absurd to think that the risk or polygenic certainty in these types of traits can be estimated.

Furthermore, with the practice of selecting embryos for favourable traits (if it were possible), an extraordinary range of options and possibilities would be opened for an attempted enhancement of human beings, and would feed fantasies such as the perfect baby, selection for physical characteristics, body optimization, etc., a whole spiral of future applications that would go against dignity by turning human embryos into objects that can be manipulated, chosen or discarded.

Finally, going back to the beginning, the use of PGD to eliminate defective embryos and choose those considered good is already in itself a eugenic technology. Regardless of what is intended, it is no more ethically reprehensible to select embryos that guarantee a super-intelligent child than to eliminate others for being a carrier of a possible disease. Eugenics, whether positive or negative, or referring to Mendelian or polygenic systems, is still eugenics.

Nicolás Jouve

Professor Emeritus of Genetics at the University of Alcala

Bioethics Observatory – Catholic University of Valencia

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