Can Genetic Engineering Overcome Inbreeding (homozygosity) Among a Ruling Family Indefinitely?

Question

Premise

In the near future, a cult-like ruling family worships symmetry and condemns asymmetry. By association, they are condemning much of nature as there are many instances of asymmetry in nature (crooked trees, irregular shapes of clouds, ect). To further "defy" asymmetry and nature they take control of a modern industrialized nation and arrange their royal marriages based on consanguinity from the beginning of their reign and for many subsequent generations. This time period may well span hundreds of years.

I was pleasantly surprised to find a similar post here:

How to negate the effects of long-term close relative inbreeding in a ruling dynasty?

Though the time seemed to be more of an ancient setting, it was a helpful analog. Yet, it should be noted that my core question of genetic engineering's potential role in this matter remains unresolved.

Problem

If natural selection were to run its course, then over time the long run propensity of the ruling family's heirs that did not have any harmful traits will approach zero. This is due to inbreeding having the effect of increasing the relative proportion of homozygotes to heterozygotes. I'm not familiar with bio-statistics, so I'm not sure if this happens at a geometric rate or an exponential rate. Technical details aside, since the ruling family will be ruling indefinitely or at least for centuries, inbreeding will most likely create many genetic "weak-links".

Attempted Solution

By utilizing present or near-future genetic engineering, the ruling family wishes to counteract the harm that may result from inbreeding from things such as having two recessive alleles. I have two specific implementations in mind:

1. The ruling family first "perfects" their genomes (becoming immune to all diseases/cancers/deformations) before inbreeding and hope that no matter which combination of traits are inherited, the offspring will be strong.

2. Micro-manage each conception and "pre-ordain" the desired trait combinations. (Presumably more involved than choosing eye color?) And assuming no outside DNA is ever introduced.

Question

In the present day/near future, if all moral limitations were lifted, how feasible would the above solutions be? How robust could we expect this kind of solution to be; would there be inherent random mutations that no amount of genetic engineering could address? If the consensus is one or both are not realistic, then what needs to happen in terms of technology to facilitate the goal of prolonged inbreeding?

Further Clarification

• other genetic engineering solutions are welcome
• Goal: A solutions that strikes a good balance between being realistic and awe/fear-inspiring
• Budget: Unlimited
• Era: present, near future
• Moral restrictions: little to none
• Duration: ideally indefinitely (as the title suggests), or at least 500 years
• Inbreeding type: immediate relatives (seen as more "symmetric")

Answer 1

Yes, "genetic engineering" can solve the problem.

First and most simply, you could just flip a coin and clone either the mother or the father (or make the gender their choice), thus zero mutations from the parent stock.

Second and more complex, the problem is mutation due to miscopying of a genome, or a poor choice of inheritance. With genetic engineering (even today) we can specify every letter of the genome and simply manufacture it that way.

For your purposes, an inventory of the genes of the ruling family can act as a library of allowable alleles (variants of a given gene) and gene segments, and a random (or intentional) selection of each part, given the founding library, could be the only allowable "persons" to be born.

In the event such a person turns out to have an undesirable trait due to some untested combination of allowable genes, Their combinations can be flagged as suspect, or if a combo appears multiple times as suspect, flagged as prohibited in the library.

Answer 2

The way to do this most efficiently is to bank sperm from the Most Excellent Ruler, and arrange that he be the father for serial generations, each with his own daughter / granddaughter.

Consider that 1st generation daughters are 50% most excellent, 2cond generation 75%, 3d is 87.5% and by 6th generation you are 98.44% Most Excellent Ruler genes. Of course a little scrambling might happen by meiosis etc but there will not be truly new genetic material introduced. These 6th generation descendants are like an inbred strain of lab mice, free of genetic disease and they may now breed freely with each other. Mutational events remain possible, of course and it might be safest to stick to the frozen sperm of the Most Excellent Ruler, thus reducing the chance for mutation by half. Do not worry about running out of banked sperm - he froze away an enormous amount.

A benefit from this method is that there can be many 1st generation daughters (of different mothers) and so the project can be done in parallel with many generations growing up at the same time. If the original mother has a disease causing recessive gene it will not be important because there is no chance for brother-sister matches and it will be diluted out along with her DNA.

In the (extremely unlikely!) event that the Most Excellent Ruler has a disease-causing recessive gene, the progeny carrying double recessives will become evident along the way. The dangerous gene will be identified and double recessives culled. Once you know that dangerous gene is present in the banked sperm one could correct it with genetic engineering by inserting the non-disease dominant copy of that gene from the Most Excellent Ruler. But the gene would persist in the banked sperm. Better and cheaper would be sorting out and disposing of sperm that carry that recessive gene.

I am not confident one can nondestructively identify various genes in sperm. Once the recessive genes of interest were known it might be necessary to grow embryos in vitro until a cell could be samples without destroying the embryo, to certify that dangerous genes were not present. In the unfortunate instance that the Ruler carried multiple recessive genes this would be cumbersome and would need to be done with each successive generation to avoid reintroducing those genes from the banked sperm. If that were the case (multiple recessives in the sperm) once one achieved near purity in the 6th or subsequent generation, one could allow a male to reach adulthood and be the new sperm donor for all subsequent generations. His genome (and sperm) would represent the genome of the Ruler purged of recessive genes.

Answer 3

The simplest and most effective genetic engineering solution is a technology widely used today called Preimplantation Genetic Diagnosis. The concept is relatively simple and has been around for decades now. You take eggs and sperm from the future mother and father and perform in-vitro fertilization to produce many embryos. You allow the embryos to divide a few times to produce more cells and then you extract a cell from each embryo. You take the DNA of this one cell and analyze it to determine the genetics of the rest of the embryo and the potential child that it will produce. Now you can simply choose to implant the embryo whose genetics you like the most. A side effect of this procedure is you can also determine the sex and potentially other non-health related phenotypic traits of the child.

PGD isn't widely used for a few reasons, but I think it would be a perfect fit for your ruling dynasty. First, it's only particularly useful for couples with a high-risk of passing on hereditary diseases. Second, it’s quite expensive. Third, many people have ethical concerns with discarding many fertilized embryos. It perhaps isn’t the most fanciful genetic engineerign technology, but it’s certainly the most realistic for a near future scenario.