Polygenic Screening: What’s the use?

A theoretical framework predicts that using polygenic screening to select embryos against traits that depend on many genes has few benefits.
  1. Jason M Fletcher
  2. Yuchang Wu
  3. Qiongshi Lu  Is a corresponding author
  1. Department of Sociology, University of Wisconsin-Madison, United States
  2. La Follette School of Public Affairs, University of Wisconsin-Madison, United States
  3. Center for Demography of Health and Aging, University of Wisconsin-Madison, United States
  4. Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, United States

Using genetic tests to select ‘designer babies’ has been a subject of science fiction for generations, but it is now getting closer to becoming a reality. Like in many other areas of science, techniques are progressing much faster than ethical and policy discussions (Conley and Fletcher, 2017). Indeed, many parents already genetically screen embryos produced using in vitro fertilization (IVF) to avoid passing on genetic variants that are known to directly cause genetic disorders (Baruch et al., 2008).

However, the plummeting cost of genetic sequencing and the sophistication of the tools used to predict characteristics based on the genetics of an individual will soon make it possible to screen for ‘complex traits’ – this is, traits that depend on many genes. This type of analysis is called polygenic screening. In short, it assesses the probability of an embryo exhibiting a trait (such as a health condition) based on the collection of genetic variants it carries that are known to influence that trait. Polygenic screening could allow couples to produce several embryos through IVF, check how likely each one is to manifest one or several complex traits, and, based on that information, decide which embryo to implant. Unlike screening for conditions that depend on a single gene, however, polygenic screening cannot always guarantee that an embryo will manifest a condition. The traits that can be tested for using polygenic screening include many health outcomes, but also characteristics that are more controversial to target, such as the IQ of a future baby (Lázaro-Muñoz et al., 2021).

Now, in eLife, Todd Lencz (Zucker School of Medicine at Hofstra/Northwell and Northwell Health), Shai Carmi (Hebrew University of Jerusalem) and colleagues – including Daniel Backenroth (Hebrew University) as joint first author with Lencz – report on the usefulness of polygenic screening when testing for complex health traits, such as schizophrenia and Crohn’s disease (Lencz et al., 2021). Briefly, the utility of screening will depend on the predictive accuracy of the genetic tests performed and, more subtly, on the goal of the testing as well as the setting – that is, who specifically is being tested, and for what.

Lencz et al. largely take predictive accuracy as a given (but see Fletcher et al., 2021 for issues of accuracy), and employ a theoretical framework to ask deeper questions about the usefulness of several strategies that can be used when selecting embryos. First, Lencz et al. assume that a hypothetical couple produces several viable embryos via IVF. The probability of each of those embryos having a specific complex trait (for example, a given health condition) can be determined using polygenic screening. Based on these probabilities, the couple must then choose which embryo to implant. Starting from these assumptions, Lencz et al. compare the utility of different approaches to selection. Finally, Lencz et al. use genome data from schizophrenia and Crohn’s disease case-control studies to simulate virtual couples and their offspring and confirm their predictions.

Lencz et al. found that, in general, polygenic screening is not very useful when it targets complex health traits. This is because most selections occur between embryos with the same parents, which substantially limits both genetic and environmental variability. Thus, when selecting for specific characteristics, there is only a small number of possible outcomes, which reduces the usefulness of any selection regime. But, within this constraint, focusing on binary traits (for example, an embryo having or not having a disease) illuminates an important asymmetry in the utility of selection. Take, for example, the case of a couple having to select one of five embryos for implantation. The benefits of ruling out the one or two embryos with the highest risk scores, and then selecting from the remaining three or four embryos by chance are small. This is because although a couple is choosing at random between three embryos that do not have the highest risk of the disease, each of them could still be at a moderate risk of having the disease. Instead, a better strategy is to pick the embryo with the lowest risk score.

However, this result provides the first reason why parents, if they are well-informed, are unlikely to perform polygenic screening. Assuming that the negative attitudes most Americans have against enhancing traits through gene editing extend to genetic screening, parents are likely to want to screen embryos to avoid disease, but are probably against choosing the ‘best’ embryo (Scheufele et al., 2017).

Even if parents (counter to intuition) did want to choose the ‘best’ embryo, deciding which is the ‘best’ soon becomes an impossible task. Lencz et al. only consider the situation where parents are choosing between embryos more or less likely to exhibit one or two complex traits; but what happens when several traits, each dependent on many genes, are of interest? A decrease in the risk of one health condition, for example, could lead to an increase in the risk of another. Trading off risks between schizophrenia and Crohn’s disease would be difficult, but when other characteristics such as genetic risks for height, IQ, and eye color are thrown into the mix, the decision becomes impossible. This ‘paradox of choice’ is a second reason that parents will not choose polygenic screening if they are properly informed about it (Schwartz, 2004).

For both of these reasons, the analysis by Lencz et al. places critical focus on the lack of utility of genetic screening for complex traits, and the findings are an incredibly important contribution for science and for public and policy discussions. Nevertheless, a number of questions about the value of polygenic screening still remain. Lencz et al. answer the (constrained) question of which embryo to choose if you must choose one. Indeed, if there are five embryos with similar risks to pick from, Lencz et al. assume that parents will select one randomly. A related question is whether these parents should implant one of the five embryos they already have, or wait to use others. This may be answered using a method that predicts whether a couple are likely to produce a lower-risk embryo than the ones they already have, based on the parents’ genetic information (Chen et al., 2020).

An obvious next step will be to study actual couples (and not virtual couples as done by Lencz et al.) because couples in the real world are likely to be more genetically similar than couples chosen at random (Domingue et al., 2014; Conley et al., 2016). Like the selection question raised by Lencz et al., this use of polygenic screening opens a large set of ethical questions as well as questions about the utility of the approach that are not yet fully answered.

References

  1. Book
    1. Conley D
    2. Fletcher J
    (2017)
    The Genome Factor
    Princeton University Press.
  2. Book
    1. Schwartz B
    (2004)
    The Paradox of Choice: Why More Is Less
    New York: Ecco.

Article and author information

Author details

  1. Jason M Fletcher

    Jason M Fletcher is in the Department of Sociology, La Follette School of Public Affairs and Center for Demography of Health and Aging at the University of Wisconsin-Madison, Madison, United States

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8843-0563
  2. Yuchang Wu

    Yuchang Wu is in the Center for Demography of Health and Aging and Department of Biostatistics and Medical Informatics at University of Wisconsin-Madison, Madison, United States

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6985-3998
  3. Qiongshi Lu

    Qiongshi Lu is in the Center for Demography of Health and Aging and Department of Biostatistics and Medical Informatics at University of Wisconsin-Madison, Madison, United States

    For correspondence
    qlu@biostat.wisc.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4514-0969

Publication history

  1. Version of Record published: October 12, 2021 (version 1)

Copyright

© 2021, Fletcher et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,488
    Page views
  • 61
    Downloads
  • 1
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jason M Fletcher
  2. Yuchang Wu
  3. Qiongshi Lu
(2021)
Polygenic Screening: What’s the use?
eLife 10:e73193.
https://doi.org/10.7554/eLife.73193

Further reading

    1. Evolutionary Biology
    2. Genetics and Genomics
    Tianzhu Xiong et al.
    Research Article Updated

    Hybridization is a major evolutionary force that can erode genetic differentiation between species, whereas reproductive isolation maintains such differentiation. In studying a hybrid zone between the swallowtail butterflies Papilio syfanius and Papilio maackii (Lepidoptera: Papilionidae), we made the unexpected discovery that genomic substitution rates are unequal between the parental species. This phenomenon creates a novel process in hybridization, where genomic regions most affected by gene flow evolve at similar rates between species, while genomic regions with strong reproductive isolation evolve at species-specific rates. Thus, hybridization mixes evolutionary rates in a way similar to its effect on genetic ancestry. Using coalescent theory, we show that the rate-mixing process provides distinct information about levels of gene flow across different parts of genomes, and the degree of rate-mixing can be predicted quantitatively from relative sequence divergence (FST) between the hybridizing species at equilibrium. Overall, we demonstrate that reproductive isolation maintains not only genomic differentiation, but also the rate at which differentiation accumulates. Thus, asymmetric rates of evolution provide an additional signature of loci involved in reproductive isolation.

    1. Genetics and Genomics
    Oguz Kanca et al.
    Research Advance Updated

    Previously, we described a large collection of Drosophila strains that each carry an artificial exon containing a T2AGAL4 cassette inserted in an intron of a target gene based on CRISPR-mediated homologous recombination. These alleles permit numerous applications and have proven to be very useful. Initially, the homologous recombination-based donor constructs had long homology arms (>500 bps) to promote precise integration of large constructs (>5 kb). Recently, we showed that in vivo linearization of the donor constructs enables insertion of large artificial exons in introns using short homology arms (100–200 bps). Shorter homology arms make it feasible to commercially synthesize homology donors and minimize the cloning steps for donor construct generation. Unfortunately, about 58% of Drosophila genes lack a suitable coding intron for integration of artificial exons in all of the annotated isoforms. Here, we report the development of new set of constructs that allow the replacement of the coding region of genes that lack suitable introns with a KozakGAL4 cassette, generating a knock-out/knock-in allele that expresses GAL4 similarly as the targeted gene. We also developed custom vector backbones to further facilitate and improve transgenesis. Synthesis of homology donor constructs in custom plasmid backbones that contain the target gene sgRNA obviates the need to inject a separate sgRNA plasmid and significantly increases the transgenesis efficiency. These upgrades will enable the targeting of nearly every fly gene, regardless of exon–intron structure, with a 70–80% success rate.